Several spleen tyrosine kinase–coupled C-type lectin receptors (CLRs) have emerged as important pattern recognition receptors for infectious danger. Because encounter with microbial pathogens leads to the simultaneous ligation of several CLRs and TLRs, the signals emanating from different pattern recognition receptors have to be integrated to achieve appropriate biological responses. In this review, we briefly summarize current knowledge about ligand recognition and core signaling by Syk-coupled CLRs. We then address mechanisms of synergistic and antagonistic crosstalk between different CLRs and with TLRs. Emerging evidence suggests that signal integration occurs through 1) direct interaction between receptors, 2) regulation of expression levels and localization, and 3) collaborative or conflicting signaling interference. Accordingly, we aim to provide a conceptual framework for the complex and sometimes unexpected outcome of CLR ligation in bacterial and fungal infection.

The immune system identifies invading microbial pathogens by conserved microbial motifs, known as pathogen-associated molecular patterns (PAMPs). For any given pathogen a combination of such PAMPs is recognized by pattern recognition receptors (PRRs) on innate immune cells. Detection of a pathogen by a combination of receptors ensures redundancy and results in lower likelihood for immune evasion by the pathogen and robustness against genetic diversity in the host. Furthermore, engagement of a pathogen-specific set of receptors allows tailoring of the immune response to protect the body against specific infections.

TLRs are the best studied family of PRRs expressed on innate immune cells. Ten functional TLRs are known in humans, and twelve have been described in mice. Interactions of TLRs and crosstalk of TLR signaling have been studied for almost two decades. C-type lectin receptors (CLRs) as another major group of PRRs have entered the field later, but their investigation has gained much momentum in the last decade. Many studies have been conducted on CLRs assigned to the so-called dendritic cell (DC)–associated C-type lectin (Dectin)-1 or Dectin-2 clusters, localized within the NK cell gene cluster on human chromosome 12 or mouse chromosome 6 (13). Several excellent reviews on the function of these CLRs in antimicrobial defense and homeostasis are available (4, 5). In this review we summarize the current knowledge about signaling downstream of the activating CLR Dectin-1 (Clec7a), Dectin-2 (human Clec6a, mouse Clec4n), macrophage-inducible C-type lectin (Mincle; Clec4e), and macrophage C-type lectin (Mcl; Clec4d) that is largely dependent on the kinase spleen tyrosine kinase (Syk). Table I provides an overview of defined ligands and microorganisms bound by this group of PRRs. In addition to microbial carbohydrate and glycolipid structures acting as PAMPs, several CLRs bind endogenous ligands such as SAP130 released by dying cells or cholesterol crystals. Thus, these CLRs are involved in homeostatic responses and inflammatory conditions (69), in addition to host response to pathogens and commensals (1012). CLR-induced APC activation directs Th cell differentiation [see Geijtenbeek and Gringhuis (13) for review], and synthetic ligands for CLRs are under development as adjuvants (14, 15). Bacteria and fungi can express more than one CLR ligand, and therefore simultaneous engagement of CLRs during recognition of microbial pathogens is likely. Additionally, concurrent activation of TLRs and CLRs will occur, leading to synergistic and antagonistic responses with sometimes unexpected outcomes. For a generalized concept of signal integration in innate immunity, we refer to a recent publication by Elinav and colleagues (16). With regard to CLR signaling, there is evidence that Dectin-1, Dectin-2, Mincle, and Mcl not only act as activating PRRs, but they are particularly important for regulation and tailoring of immune responses. In this review, we discuss the interactions following simultaneous engagement of several CLRs and TLRs. Conceptually, we propose that such signal integration can occur on different levels, which are discussed in this structured review: 1) contact between receptors, with possible consequences for ligand binding, receptor stability, or localization; 2) control of receptor expression levels, adjusting the responsiveness; 3) collaborative signaling, leading to synergistic responses; and 4) conflicting signaling, tailoring the inflammatory response.

Table I.
Overview of microbial and endogenous ligands of Syk-coupled CLRs
LigandCommentsReferences
Mcl (Clec4d) 
 Klebsiella pneumoniae Protective role in infection model (158
 Mycobacterium tuberculosis, Mycobacterium bovis Protective role in infection model (91
 TDM from Mycobacterium spp. Mouse, human, not guinea pig (67, 70, 87, 122
 Blastomyces dermatitidis Mouse (94
 Candida albicans Controversial role in infection models (92, 93
 Cryptococcus neoformans Protective role in infection model (159
Mincle (Clec4e) 
 Cholesterol crystals (endogenous) CRAC motif, human, not mouse/rat (86
 SAP130, dead cells (endogenous) Ca2+-independent, VEGQ motif (69, 157, 160
 Helicobacter pylori Human (161
 K. pneumoniae Protective role in infection model (162
 Streptococcus pneumoniae Mouse (163
 M. tuberculosis, M. bovis, Mycobacterium smegmatis Controversial role in infection models (8890, 97, 98
 Cyclopropane–fatty acid α-glucosyl diglyceride from Lactobacillus plantarum Mouse/human (164
 β-Gentiobiosyl diaglycerides from M. tuberculosis (H37Ra) Mouse, not human (165
 TDM from Mycobacterium spp. Ca2+-dependent, mouse/human/guinea pig/cow (7072, 87, 97, 98, 105, 122, 166
 Synthetic trehalose diesters, including TDB, corynomycolates Mouse/human (7072, 74, 81, 98, 122, 167169
 Synthetic trehalose monoesters Mouse (82
 Glycerol monomycolate (MMG, GroMM) Human, not mouse (85
 Brartemicin Mimicks glycolipid binding (83
 C. albicans Mouse/human (116, 166, 170
 Cladophialophora carrionii Human (50
 Fonsecaea pedrosoi, Fonsecaea monophora, Fonsecaea compacta Mouse/human (50, 145, 153
 Malassezia furfur, glycolipid Mouse (167, 171
Dectin-2 (Clec4n/Clec6a) 
 CD4+CD25+ T cell ligand (endogenous) Mouse (172
 K. pneumoniae, K55 LPS Mouse (173
 S. pneumoniae, serotype 3 Protective role in infection model (173, 174
 Mycobacterium spp., mannose-capped lipoarabinomannan Mouse (173, 175
 Aspergillus fumigatus Mouse (176
 B. dermatitidis Mouse (94, 177
 C. albicans, Candida glabrata, α-mannan, hyphae Mouse (68, 99, 103, 173, 178
 Coccoides posadasii Mouse (177
 C. neoformans Mouse (179
 F. pedrosoi Mouse (153
 Histoplasma capsulatum Mouse (173, 177
 Malassezia furfur, O-linked mannoprotein Mouse (167
 Microsporum audouinii, hyphae Mouse (68
 Paracoccoides brasiliensis Mouse (173
 Trichophyton rubrum, hyphae Mouse (68, 180
 Saccharomyces cervisiae Mouse (173
 Schistosoma mansoni Mouse (108
 Dermatophagoides pteronyssinus, house dust mite Mouse (181
Dectin-1 (Clec7a) 
 T cell ligand (endogenous) Mouse (182
 Ligand on parenchymal/ inflammatory cells in liver (endogenous) Mouse (183
 Vimentin (endogenous) Human (184
 Haemophilus influenzae, nontypeable Mouse/human (185, 186
 Mycobacterium spp. Mouse/human (33, 187, 188
 A. fumigatus, maturing conidia, germ tubes Mouse/human, protective role in infection model (189192
 C. albicans, β-1,3 glucan, yeast Mouse/human, protective role in infection model (31, 68, 124, 193, 194
 Coccidioidis posadasii, Coccidioidis immitis Mouse (177, 195
 H. capsulatum Mouse (40, 177, 196
 M. audouinii, yeast Mouse (68
 Penicillium marneffei Mouse (197
 Pneumocystis carnii Mouse (198
 T. rubrum, yeast Mouse/human (68, 180, 199
 Trichosporon asahii Mouse (200
 S. cervisiae, glucan Mouse (198
 Curdlan, particulate β-glucan  (201, 202
 Laminarin, soluble β-glucan Blocking, nonactivating (34, 35, 201, 202
 Zymosan Nondepleted zymosan also binds TLR2 (126, 201203
 Ju-6, hexavalent lactoside Non–β-glucan, not blocked by Laminarin (204
LigandCommentsReferences
Mcl (Clec4d) 
 Klebsiella pneumoniae Protective role in infection model (158
 Mycobacterium tuberculosis, Mycobacterium bovis Protective role in infection model (91
 TDM from Mycobacterium spp. Mouse, human, not guinea pig (67, 70, 87, 122
 Blastomyces dermatitidis Mouse (94
 Candida albicans Controversial role in infection models (92, 93
 Cryptococcus neoformans Protective role in infection model (159
Mincle (Clec4e) 
 Cholesterol crystals (endogenous) CRAC motif, human, not mouse/rat (86
 SAP130, dead cells (endogenous) Ca2+-independent, VEGQ motif (69, 157, 160
 Helicobacter pylori Human (161
 K. pneumoniae Protective role in infection model (162
 Streptococcus pneumoniae Mouse (163
 M. tuberculosis, M. bovis, Mycobacterium smegmatis Controversial role in infection models (8890, 97, 98
 Cyclopropane–fatty acid α-glucosyl diglyceride from Lactobacillus plantarum Mouse/human (164
 β-Gentiobiosyl diaglycerides from M. tuberculosis (H37Ra) Mouse, not human (165
 TDM from Mycobacterium spp. Ca2+-dependent, mouse/human/guinea pig/cow (7072, 87, 97, 98, 105, 122, 166
 Synthetic trehalose diesters, including TDB, corynomycolates Mouse/human (7072, 74, 81, 98, 122, 167169
 Synthetic trehalose monoesters Mouse (82
 Glycerol monomycolate (MMG, GroMM) Human, not mouse (85
 Brartemicin Mimicks glycolipid binding (83
 C. albicans Mouse/human (116, 166, 170
 Cladophialophora carrionii Human (50
 Fonsecaea pedrosoi, Fonsecaea monophora, Fonsecaea compacta Mouse/human (50, 145, 153
 Malassezia furfur, glycolipid Mouse (167, 171
Dectin-2 (Clec4n/Clec6a) 
 CD4+CD25+ T cell ligand (endogenous) Mouse (172
 K. pneumoniae, K55 LPS Mouse (173
 S. pneumoniae, serotype 3 Protective role in infection model (173, 174
 Mycobacterium spp., mannose-capped lipoarabinomannan Mouse (173, 175
 Aspergillus fumigatus Mouse (176
 B. dermatitidis Mouse (94, 177
 C. albicans, Candida glabrata, α-mannan, hyphae Mouse (68, 99, 103, 173, 178
 Coccoides posadasii Mouse (177
 C. neoformans Mouse (179
 F. pedrosoi Mouse (153
 Histoplasma capsulatum Mouse (173, 177
 Malassezia furfur, O-linked mannoprotein Mouse (167
 Microsporum audouinii, hyphae Mouse (68
 Paracoccoides brasiliensis Mouse (173
 Trichophyton rubrum, hyphae Mouse (68, 180
 Saccharomyces cervisiae Mouse (173
 Schistosoma mansoni Mouse (108
 Dermatophagoides pteronyssinus, house dust mite Mouse (181
Dectin-1 (Clec7a) 
 T cell ligand (endogenous) Mouse (182
 Ligand on parenchymal/ inflammatory cells in liver (endogenous) Mouse (183
 Vimentin (endogenous) Human (184
 Haemophilus influenzae, nontypeable Mouse/human (185, 186
 Mycobacterium spp. Mouse/human (33, 187, 188
 A. fumigatus, maturing conidia, germ tubes Mouse/human, protective role in infection model (189192
 C. albicans, β-1,3 glucan, yeast Mouse/human, protective role in infection model (31, 68, 124, 193, 194
 Coccidioidis posadasii, Coccidioidis immitis Mouse (177, 195
 H. capsulatum Mouse (40, 177, 196
 M. audouinii, yeast Mouse (68
 Penicillium marneffei Mouse (197
 Pneumocystis carnii Mouse (198
 T. rubrum, yeast Mouse/human (68, 180, 199
 Trichosporon asahii Mouse (200
 S. cervisiae, glucan Mouse (198
 Curdlan, particulate β-glucan  (201, 202
 Laminarin, soluble β-glucan Blocking, nonactivating (34, 35, 201, 202
 Zymosan Nondepleted zymosan also binds TLR2 (126, 201203
 Ju-6, hexavalent lactoside Non–β-glucan, not blocked by Laminarin (204

Ligand binding to either the extracellular or endosomal ectodomain of TLRs leads to dimerization of the cytoplasmic Toll/IL-1R (TIR) domain. Dimerization can occur as both homo- or heterodimers (TLR1/TLR2 and TLR2/TLR6). Adaptor proteins are subsequently recruited by TIR–TIR interactions. Downstream signaling is induced dependent on MyD88 (engaged by all TLRs except TLR3) and/or TIR domain–containing adaptor protein inducing IFN-β (TRIF, engaged by TLR3 and TLR4). Activation of NF-κB and IFN regulatory factors (IRF) are central events downstream of MyD88 and TRIF (17) (Fig. 1). Synergistic responses have been described for combination of MyD88 and TRIF-dependent TLR ligands (18, 19). C-type lectins are a protein superfamily with >1000 members belonging to 17 subgroups based on structural and ligand-binding features (20). The receptors in the Dectin-1 and Dectin-2 cluster, of which many contribute to innate immunity, belong to the related subgroup II (asialoglycoprotein and DC receptors, Ca2+ binding) and subgroup V (NK cell receptors, non-Ca2+ binding). Ligand binding is mediated by the C-type lectin domain (CTLD) (21), often containing a QPD or EPN motif. Dectin-1 (Clec7a, CD369, Clecsf12), Dectin-2 (human CLEC6A, mouse Clec4n, Clecsf10), Mincle (Clec4e, Clecsf9), and Mcl (Clec4d, CD368, Clecsf8) are activating receptors that share signaling via ITAM and Syk. Dectin-1 recruits Syk via a hemITAM motif, whereas Mcl, Mincle, and Dectin-2 associate with the ITAM-containing FcRγ-chain. Downstream of Syk, activation of the canonical NF-κB pathway is dependent on formation of the Card9/Bcl10/Malt1 complex (4) (Fig. 1).

FIGURE 1.

Schematic comparison of CLR and TLR signaling. Transmembrane receptors (green), adapter proteins (blue), kinases (red), and transcription factors (orange) are shown. Examples of target genes from overlapping and distinct transcriptional responses are shown. The CLR Dectin-1, Dectin-2, and Mincle share canonical signaling via FcRγ, Syk, and the CBM complex (left). All TLRs except TLR3 recruit the adapter protein MyD88; the adapter TRIF is required for signaling by TLR3 and TLR4 (right).

FIGURE 1.

Schematic comparison of CLR and TLR signaling. Transmembrane receptors (green), adapter proteins (blue), kinases (red), and transcription factors (orange) are shown. Examples of target genes from overlapping and distinct transcriptional responses are shown. The CLR Dectin-1, Dectin-2, and Mincle share canonical signaling via FcRγ, Syk, and the CBM complex (left). All TLRs except TLR3 recruit the adapter protein MyD88; the adapter TRIF is required for signaling by TLR3 and TLR4 (right).

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Consistent with the shared activation of NF-κB and MAPK by TLR and CLR, ligands for both types of PRRs induce an overlapping set of proinflammatory cytokines and chemokines. However, there is also evidence for selective and preferential target gene expression. A limited number of microarray studies have compared stimulation with CLR ligands such as β-glucans (Dectin-1) or trehalose dibehenate (TDB; Mincle) with TLR ligands such as Pam3 (TLR2), LPS (TLR4), or CpG (TLR9) (2225). Whereas TLR9 ligation induces strong IL-12 production associated with Th1 generation, the induction of IL-1β, IL-6, and IL-23 after engagement of Syk-Card9–coupled CLRs is observed across cell types and species, promoting the differentiation of IL-17–producing CD4+ T cells (23, 24, 26, 27). Remarkably, to date there is only very limited information about the effects of combined stimulation of CLR and TLR pathways on global gene expression.

We concentrate in the following on reviewing the current literature on Dectin-1 and the Dectin-2, Mcl and Mincle.

Dectin-1 and the Dectin-1 subfamily.

Dectin-1 is the best studied receptor in the Dectin-1 family; signaling events downstream of Dectin-1 ligation are often regarded as prototypic for Syk-coupled CLRs (28, 29). Dectin-1 recognizes β-glucans in fungal and mycobacterial cell walls in a Ca2+-independent manner (3033) (see Table I). β-Glucans bind to Dectin-1 homodimers, and ligand binding has been suggested to induce oligomerization (34). Whereas particulate ligands result in formation of a “phagocytic synapse,” stimulation with a soluble ligand does not induce a response (35). Dectin-1 signals via its internal hemITAM motif (single YxxL/I motif) (36), which is phosphorylated upon ligand binding. Recruitment of Syk to the phosphorylated hemITAM is pivotal for Dectin-1 responses (37) and requires a phosphatase-independent chaperone function of SHP-2 (38). Lipid raft formation has been shown to be important for Syk recruitment (39, 40). Downstream of Syk, canonical NF-κB signaling is dependent on the activation of phospholipase C (PLC)γ2 (39), phosphorylation of protein kinase C (PKC)δ (41, 42), and formation of the Card9/Bcl10/Malt-1 complex (43, 44), which involves the ubiquitin ligase Trim62 (45). Different NF-κB subunits are activated following Dectin-1 ligation through Syk and Raf-1 as reviewed in detail by Geijtenbeek and Gringhuis (46). So far, Syk-independent signaling via Raf-1 has only been described after Dectin-1 ligation in human DCs (4749). IRF1 (50) and IRF5 (51) are further transcription factors induced. Phosphorylation of the MAPK p38 and JNK appears to be partially Syk-independent (26, 38, 52); in contrast, phosphorylation of the MAPK ERK requires Syk and is mediated by Card9 and H-Ras (53, 54). Activation of ERK is critical for reactive oxygen species (ROS) production, which has been linked to induction of autophagy (55) and to assembly of the Nlrp3 inflammasome (5658). Assembly of a noncanonical Malt1/Caspase-8/ASC inflammasome triggered by Dectin-1 has as well been described (5961). In addition to its requirement for assembly of the Card9/Bcl10/Malt-1 complex, PLCγ2 induces Ca2+ flux triggering the classical calcineurin/NFAT pathway that directly induces Egr1 expression (39, 62) and is required for antifungal defense (63).

Dectin-2 cluster: Dectin-2, Mcl, Mincle.

The genes encoding these receptors are localized adjacent to each other in the Dectin-2 cluster on human chromosome 12/mouse chromosome 6 (3, 6466). Dectin-2 and Mcl likely arose from gene duplication of Mincle (64, 67). Dectin-2, Mincle, and Mcl do not contain a cytoplasmic signaling motif, but instead they associate with the ITAM (YxxL/I,YxxL/I)-containing adaptor FcRγ-chain (6, 6769) (Fig. 1).

Whereas ligands of Dectin-2 and Mincle are diverse and not always structurally characterized, Dectin-2, Mincle, and Mcl all recognize ligands on fungi and mycobacteria in a Ca2+-dependent manner (see Table I). Several studies have addressed the structural requirements for interaction of Mincle with the mycobacterial cord factor trehalose dimycolate (TDM) or synthetic trehalose esters (7074), which have recently been summarized in excellent reviews (7577). Mincle binds the trehalose part of the cord factor with its Ca2+-dependent sugar-binding pocket, and its structure revealed a hydrophobic groove that likely accommodates the lipid component of TDM or TDB. The recent interest in Mincle ligands for adjuvant development (7880) has engendered the chemical synthesis of multiple glycolipids, which help to determine the requirements for receptor binding and macrophage activation (8184). Different from cord factor binding, recognition of the nucleoprotein SAP130 is Ca2+-independent (6). Human and murine Mincle have divergent ligand specificities, for example, for glycerol monomycolates (82, 85) or cholesterol crystals (86). The CTLD of Mcl is much less conserved among species than the Mincle CTLD; consequently, Mcl appears to be a functional TDM receptor in mice (67), but not, for example, in guinea pigs (87), suggesting divergent physiological roles of Mcl between species. Mincle- or Mcl-deficient mice showed mostly moderate phenotypes in mycobacterial (8891) or fungal infection models (9294) compared with knockouts of the downstream Card9 (43, 95), indicating receptor redundancy. It is quite possible that double-deficient mice will show more severe phenotypes. Whereas both Dectin-2 and Mcl have phagocytic properties (66, 68), Mincle was described to be dispensable for glycolipid uptake (96), although required for cytokine production after glycolipid stimulation (97, 98). Ligand binding to Dectin-2 and Mincle leads to engagement of the FcRγ–Syk–PLCγ2–PKCδ–Card9 axis and activation of the canonical NF-κB pathway similar to Dectin-1 (6, 42, 98100) (Fig. 1). Gringhuis et al. (101) described that Dectin-2 engagement specifically activates c-REL controlled by Malt1, in contrast to induction of all NF-κB subunits by Dectin-1 stimulation. Engagement of Dectin-2 and Mincle furthermore leads to activation of the MAPK p38, ERK, and JNK (99, 102105). ERK phosphorylation after stimulation of Dectin-2 with Candida albicans is dependent on Syk and PLCγ2 but not Card9 (100, 103). Activation of PKB (synonym Akt) is found downstream of Mincle and Dectin-2 and is dependent on PI3K (50, 106). Both Dectin-2 and Mincle ligation can lead to production of ROS and inflammasome activation (107112).

Activation of TLRs results not only from homodimer formation but also from heterodimerization. TLR2 can pair with either TLR1 or TLR6, resulting in an increased ligand spectrum (113115). Homodimeric forms of human and mouse Mincle have been described quite early (116), and recently heterodimerization of Mcl has been described with Mincle (117) and with Dectin-2 (93).

It has been controversial whether Mcl interacts directly with the adapter protein FcRγ. Mcl lacks the conserved arginine residue in the stalk region that is required for interaction of murine Mincle with FcRγ (6), and Graham et al. (92) could not find association of human Mcl with FcRγ, DAP10, or DAP12. In contrast, Miyake et al. (67) demonstrated that murine Mcl coimmunoprecipitates with FcRγ in the absence of Mincle, uniquely utilizing a hydrophilic threonine residue rather than arginine. Direct association with FcRγ was likewise found for guinea pig Mcl, which similar to human Mcl has a serine at position 38 (87). Lobato-Pascual et al. (117) showed formation of disulfide-linked Mincle–Mcl heterodimers and suggested that rat Mcl interacts with FcRγ in an indirect fashion via heterotrimer formation with Mincle. Two independent studies demonstrated that the surface expression of Mincle and Mcl on myeloid cells is interdependently stabilized by their heterodimerization (118, 119). In consequence, Mcl-deficient mice have reduced Mincle surface expression but Mcl-transgenic mice show enhanced responsiveness to TDM stimulation, and Mcl surface levels are strongly reduced in Mincle-deficient cells. The interaction of murine Mincle and Mcl requires four hydrophobic residues in the stalk region of Mincle (118). In contrast, Zhao et al. (120) neither found coimmunoprecipitation of human Mincle and Mcl coexpressed in RAW264.7 cells, nor did they observe synergistic responses. Previously, the authors had described the dimerization of human and murine Mcl with Dectin-2 and demonstrated a synergistic role of Dectin-2 and Mcl for protection in a murine C. albicans infection model (93). A phenotype in C. albicans infection had not been observed in an earlier study (92), nor was coregulation of Dectin-2 and Mcl in mice confirmed in two other reports (94, 119). Overall, there is strong evidence that Mcl is able to dimerize with related CLRs, notwithstanding some disagreement in the literature. Further studies are needed to investigate whether discrepant results can be attributed to different cell types or receptors originating from different species. Several roles for Mcl in these interactions have been suggested and are depicted in Fig. 2: 1) transcriptional regulation of Mincle expression (further discussed below); 2) posttranscriptional regulation by interdependent stabilization of Mincle surface expression (118, 119); 3) Mincle could benefit from phagocytic capacity of Mcl (117, 121); 4) enhanced ligand binding by heterodimerization with Dectin-2 or Mincle, leading to an increased response (93, 122); and 5) alteration of ligand specificity (121). It can be expected that molecular dynamics simulations based on existing crystal structures of Mincle and Mcl as well as further structural work will be instrumental in answering which of these models is correct.

FIGURE 2.

Mcl–Mincle cooperation at multiple levels. (A) In the absence of Mincle expression in resting macrophages, binding of TDM to Mcl is sufficient and required to induce Mincle mRNA expression. Mcl-induced Mincle expression establishes a feed-forward loop of TDM responsiveness (67). (B) Mincle and Mcl act as chaperones for each other, increasing the cell surface expression levels via enhanced transport and/or stabilization (117, 118, 147). (C) Heterodimerization of Mcl and Mincle may increase the affinity for ligands via cooperative binding. Depending on the topology of the heterodimers, ligands such as TDM may be contacted by Mincle and Mcl forming one heterodimer (left) or may connect two heterodimers together (right). Heterodimer formation could also create specific binding to ligands not recognized by the single receptors.

FIGURE 2.

Mcl–Mincle cooperation at multiple levels. (A) In the absence of Mincle expression in resting macrophages, binding of TDM to Mcl is sufficient and required to induce Mincle mRNA expression. Mcl-induced Mincle expression establishes a feed-forward loop of TDM responsiveness (67). (B) Mincle and Mcl act as chaperones for each other, increasing the cell surface expression levels via enhanced transport and/or stabilization (117, 118, 147). (C) Heterodimerization of Mcl and Mincle may increase the affinity for ligands via cooperative binding. Depending on the topology of the heterodimers, ligands such as TDM may be contacted by Mincle and Mcl forming one heterodimer (left) or may connect two heterodimers together (right). Heterodimer formation could also create specific binding to ligands not recognized by the single receptors.

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Expression of PRRs is a prerequisite for recognition of a microbial ligand. However, expression of PRRs is not uniform among different innate immune cell types and can be massively regulated by cytokines and microbial stimuli. Hence, cross-regulation of expression levels is in principle a logical mechanism for crosstalk between different PRRs and their signaling pathways. Specifically, Syk-coupled CLRs show large differences in expression between different cell types and activation states. Dectin-1 mRNA can be induced by GM-CSF and IL-4, but it is downregulated by LPS, IFN-γ, and IL-10 (123). Dectin-2 protein in monocytes increases under inflammatory conditions (124). Similarly, Mincle mRNA expression is low in resting murine macrophages and DCs but strongly inducible upon stimulation with inflammatory stimuli (64, 67, 104). Matsumoto et al. (64) identified Mincle (“macrophage inducible C-type lectin”) originally in a screen for target genes of the transcription factor C/EBPβ following LPS/IFN-γ stimulation. Mincle expression is also upregulated by its ligand TDM in a feed-forward loop through Mincle itself (98, 104), or through Mcl acting as a constitutively expressed low-affinity receptor for TDM in mice (67, 120) (Figs. 2A, 3C). It is currently unclear whether such transcriptional regulation of Mincle expression is conserved in other species that express higher constitutive levels of Mincle mRNA (50, 87, 122, 125).

FIGURE 3.

Collaborative signaling between CLRs and TLRs. (A) CR3 (CD11b/CD18) binds zymosan and H. capsulatum dependent on iC3b, triggering Syk activation and cooperates with β-glucan–induced Dectin-1 signaling for robust JNK/AP-1 activation (40). (B) TLR2 and Dectin-1 bind simultaneously to zymosan and synergize in the NF-κB activation and production of TNF, IL-23 and IL-6 (126, 136, 137). Enhanced IL-10 production downregulates IL-12 expression (144). (C) Macrophage activation in response to F. pedrosoi requires Mincle. Treatment of infected mice with TLR ligands enables the clearance of infection, suggesting that TLR-MyD88 and Mincle-Syk synergize in the upregulation of the cytokines and mediators required for killing of F. pedrosoi (145). TLR-MyD88 signals strongly enhance Mincle mRNA and protein expression, and thereby sensitize macrophages for responsiveness to Mincle ligands such as mycobacterial TDM and F. pedrosoi (104, 147). Note that TLR7 and TLR9 are localized in the endosome and are shown here as cell surface receptors for reasons of simplicity. (D) TLR-Mincle synergy in protein expression of a subset of inducible genes, most notably iNOS, is mediated by Mincle-controlled increases in translation due to p38-dependent hypusination of eIF5A. Although required for robust inflammatory responses, Mincle signaling contributes to termination and resolution of inflammation by NO-mediated inhibition of the Nlrp3 inflammasome and IL-1 release (107).

FIGURE 3.

Collaborative signaling between CLRs and TLRs. (A) CR3 (CD11b/CD18) binds zymosan and H. capsulatum dependent on iC3b, triggering Syk activation and cooperates with β-glucan–induced Dectin-1 signaling for robust JNK/AP-1 activation (40). (B) TLR2 and Dectin-1 bind simultaneously to zymosan and synergize in the NF-κB activation and production of TNF, IL-23 and IL-6 (126, 136, 137). Enhanced IL-10 production downregulates IL-12 expression (144). (C) Macrophage activation in response to F. pedrosoi requires Mincle. Treatment of infected mice with TLR ligands enables the clearance of infection, suggesting that TLR-MyD88 and Mincle-Syk synergize in the upregulation of the cytokines and mediators required for killing of F. pedrosoi (145). TLR-MyD88 signals strongly enhance Mincle mRNA and protein expression, and thereby sensitize macrophages for responsiveness to Mincle ligands such as mycobacterial TDM and F. pedrosoi (104, 147). Note that TLR7 and TLR9 are localized in the endosome and are shown here as cell surface receptors for reasons of simplicity. (D) TLR-Mincle synergy in protein expression of a subset of inducible genes, most notably iNOS, is mediated by Mincle-controlled increases in translation due to p38-dependent hypusination of eIF5A. Although required for robust inflammatory responses, Mincle signaling contributes to termination and resolution of inflammation by NO-mediated inhibition of the Nlrp3 inflammasome and IL-1 release (107).

Close modal

In addition to the sequential control of Mincle mRNA expression, Mcl also controls the surface expression of Mincle protein. As described above, Mcl was recently identified to interact with Mincle via its stalk region and to be essential for surface expression of Mincle (118, 119) (Fig. 2B). Although the molecular and kinetic details of the Mincle–Mcl interaction are not yet fully understood, it has become evident that protein interactions and protein localization are a means to control the responsiveness beyond the transcriptional level.

Many fungi and bacteria contain several different CLR ligands (see Table I) that will lead to the concurrent triggering of more than one CLR in phagocytes and DCs upon making contact with the microbes. Furthermore, scavenger receptors such as CD36, complement receptors, TLRs, and cytosolic nucleic acid sensors are engaged upon pathogen contact. Receptor crosstalk can result in synergistic or conflicting signaling, thereby modulating the immune response. Examples for experimental ligands binding to both CLRs and TLRs are nondepleted zymosan (Dectin-1–TLR2) or mannosylated O-antigens (Dectin-2–TLR4) (126, 127). Dectin-1–TLR2 crosstalk is the most extensively studied example of CLR–TLR crosstalk, mostly but not exclusively leading to synergistic responses (Fig. 3).

Dectin-1 and complement receptor 3 (CR3 or CD11b/CD18, encoded by Itgam and Itgb2) both recognize β-glucans (Fig. 3A). CR3 was described as a zymosan receptor in neutrophils (128, 129) and as a receptor for soluble β-glucan in mononuclear cells (130). The idea of Dectin-1–CR3 crosstalk is further promoted by the observation that the receptors colocalized on lipid rafts after Histoplasma capsulatum stimulation. Collaborative TNF and IL-6 responses were dependent on Syk and JNK but not NF-κB (40). CD11b can itself recruit Syk and was shown to negatively regulate TLR-mediated inflammatory responses via the E3 ubiquitin ligase Cbl-b (131, 132). Thus, CR3-Syk appears to synergize with Dectin-1 signaling, but downregulates TLR-induced responses. Very recently, Cbl-b–mediated ubiquitination and degradation of Dectin-1, Dectin-2, and Syk were demonstrated, revealing a broader role for this ubiquitin ligase in regulation of TLR and CLR signaling (133135).

Dectin-1 and TLR2 are both required to obtain strong production of TNF and IL-12 and NF-κB activation in murine macrophages and DCs after zymosan stimulation; colocalization was observed upon stimulation (126, 136) (Fig. 3B). Results were similar after stimulation with particulate β-glucans followed by ligands for TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9 (137, 138). Prolonged IκB degradation and enhanced NF-κB translocation resulted in more-than-additive production of TNF, IL-23, IL-6, and IL-10, but reduced production of IL-12 (137, 139). Syk and Card9 were required for the synergistic response (137, 140), which was similarly detected in human monocytes and macrophages (141). Of note, the synergistic signaling via Dectin-1 and TLR2 does not only result in proinflammatory cytokine production, but also in augmented secretion of anti-inflammatory IL-10 (Fig. 3B). Secretion of IL-10 is controlled by the MAPK ERK and p38, phosphorylation of mitogen- and stress-activated protein kinase 1/2, and engagement of the transcription factor CREB, consistent with induction of a regulatory phenotype and reduced activation of T cells (53, 142144).

Synergistic TNF and IL-10, but reduced IL-12 secretion, has similarly been described for simultaneous engagement of Mincle and TLR ligands (145, 146) (Fig. 3C). IL-10 can itself regulate IL-12 production in an autocrine manner as observed after costimulation of TLR2 and Mincle by synthetic ligands and mycobacteria (146). As mentioned above, TLR-derived signaling increases Mincle expression and can thereby enhance responsiveness to TDM (104, 147). This mechanism may also contribute to the beneficial effect of TLR ligands in Fonsecaea pedrosoi infection, a model for human chromoblastomycosis (145) (Fig. 3C).

An intriguing mechanism of synergistic action of TLR and Mincle signaling acting at the level of translation efficiency was revealed recently: combined stimulation of TLR2 and Mincle induced more-than-additive NO production, particularly at later stages of inflammation (107) (Fig. 3D). Protein expression of inducible NO synthase (iNOS) was mediated by Mincle-controlled increase in translation, which required p38-dependent hypusination of eIF5A. Importantly, the eIF5A-dependent NO production at later stages of inflammation inhibited Nlrp3-mediated IL-1β production, counteracting the synergistic induction of proIL-1β by TLR2 and Mincle. Blockade of eIF5A or iNOS deficiency resulted in exacerbating inflammation in TDM-induced lung granulomas and enhanced mortality, identifying Mincle as an important regulator of antimycobacterial immune responses at later stages of inflammation (107).

In addition to these acute synergistic effects of concurrent stimulation of CLRs and TLRs, Dectin-1 ligands can prime responses to subsequent stimulation by TLR ligands (49), an effect characterized as “training of innate immunity” by Netea et al. (148). These long-lasting effects of CLR signaling depend on Hif1α and mammalian target of rapamycin–dependent metabolic changes and epigenetic programming (149, 150) and are distinct from the collaborative effects described above.

Several mechanisms have been proposed to contribute to the negative regulation of cytokine production after CLR ligation. Eberle and Dalpke (52) demonstrated that suppressor of cytokine signaling (SOCS)1 is induced after stimulation with depleted zymosan (Dectin-1) and CpG (TLR9) in murine bone marrow macrophages and DCs (Fig. 4A). Socs1 induction is dependent on Syk, Pyk2, and ERK activation but is Ca2+- and NF-κB–independent. It resulted in decreased and shortened activation of NF-κB (p50 and p52) and thus reduced IL-12p40 secretion. In peritoneal macrophages, Socs1 and PIAS1 induction downstream of Dectin-1 has been described in a Ca2+-dependent manner to be dependent on the expression of Wnt5a, induced by the ROS/β-catenin axis. Socs1 and PIAS1 induction lead to reduced expression of IL-12, IL-1β, and TNF and abrogated TLR signaling via degradation of IL-1R–associated kinase (IRAK)1, IRAK4, and MyD88 (151). Downstream of Dectin-2, but not of Dectin-1, β-catenin stabilization in DCs occurs dependent on phosphorylation of LAB and leads to impaired IL-12 production (152).

FIGURE 4.

Conflicting signaling: negative regulation by CLR activation. (A) Dectin-1 triggering upregulates Socs1 through Pyk2-ERK activation, which inhibits TLR-induced IL-12 production, associated with inhibition of NF-κB activation (52). In a later study, Socs1 induction after Dectin-1 triggering was shown to depend on the β-catenin–induced secretion of Wnt5a, which in turn triggers Pyk2 via Frizzled (151). In this study, Dectin-1–induced Socs1 caused a severe loss of MyD88-IRAK4-TRAF6 proteins and unresponsiveness to TLR ligation. TLR9 is an endosomal receptor shown here in the plasma membrane for reasons of simplicity. (B) The fungal pathogen F. pedrosoi triggers both Mincle and Dectin-1 signaling. Wevers et al. (50) showed in human DC selective activation of PI3K-PKB dependent on Mincle, which interferes with Dectin-1–induced expression of IL-12 by the targeting of nuclear IRF1 for degradation through the PKB-mediated activation of the E3 ubiquitin ligase Mdm2. Of note, Mincle activation also inhibited TLR9-induced IL-12 expression through the same mechanism (50). (C) Mincle and Dectin-1 inhibit responses to LPS by downregulating the expression of the LPS coreceptor CD14. Mincle/ and Dectin-1/ mice are more susceptible to LPS shock due to excessive cytokine production. Macrophages from Dectin-1/ mice had higher CD14 and TLR4 surface expression (154), whereas in Mincle-deficient macrophages only CD14 was elevated (155). Induction of Socs1, ABIN3, and A20 by LPS, as well as the degradation of TRAF6 and Mal, was Mincle-dependent after LPS stimulation. The basis for LPS-induced Mincle/Dectin-1–dependent Syk activation is at present unknown.

FIGURE 4.

Conflicting signaling: negative regulation by CLR activation. (A) Dectin-1 triggering upregulates Socs1 through Pyk2-ERK activation, which inhibits TLR-induced IL-12 production, associated with inhibition of NF-κB activation (52). In a later study, Socs1 induction after Dectin-1 triggering was shown to depend on the β-catenin–induced secretion of Wnt5a, which in turn triggers Pyk2 via Frizzled (151). In this study, Dectin-1–induced Socs1 caused a severe loss of MyD88-IRAK4-TRAF6 proteins and unresponsiveness to TLR ligation. TLR9 is an endosomal receptor shown here in the plasma membrane for reasons of simplicity. (B) The fungal pathogen F. pedrosoi triggers both Mincle and Dectin-1 signaling. Wevers et al. (50) showed in human DC selective activation of PI3K-PKB dependent on Mincle, which interferes with Dectin-1–induced expression of IL-12 by the targeting of nuclear IRF1 for degradation through the PKB-mediated activation of the E3 ubiquitin ligase Mdm2. Of note, Mincle activation also inhibited TLR9-induced IL-12 expression through the same mechanism (50). (C) Mincle and Dectin-1 inhibit responses to LPS by downregulating the expression of the LPS coreceptor CD14. Mincle/ and Dectin-1/ mice are more susceptible to LPS shock due to excessive cytokine production. Macrophages from Dectin-1/ mice had higher CD14 and TLR4 surface expression (154), whereas in Mincle-deficient macrophages only CD14 was elevated (155). Induction of Socs1, ABIN3, and A20 by LPS, as well as the degradation of TRAF6 and Mal, was Mincle-dependent after LPS stimulation. The basis for LPS-induced Mincle/Dectin-1–dependent Syk activation is at present unknown.

Close modal

As mentioned above, Mincle is important for recognition of F. pedrosoi, but synergistic TLR stimulation and TNF production was required to clear the infection in a mouse model of chromoblastomycosis (145) (Fig. 3C). In contrast, Mincle engagement counteracted the induction of IL-12 by Fonsecaea monophora in human DCs (Fig. 4B). F. monophora simultaneously engages Dectin-1, leading to activation of IRF1 and IL-12A (IL-12p35) transcription, and Mincle. In a PI3K-PKB–dependent manner, Mincle activates the E3 ubiquitin ligase Mdm2, leading to degradation of Dectin-1–induced IRF1, thus blocking IL-12A transcription. Degradation of TLR-induced IRF1 was similarly observed. The blockade of IL-12A resulted in a shift from a protective Th1 to a detrimental Th2 response in cocultures with T cells in vitro (50). Thus, although sensing of F. pedrosoi by Mincle is required for innate protection, the negative effect on IL-12 production may interfere with the development of protective T cell immunity. Along this line, Mincle-deficient mice showed an increased Th17 response in F. pedrosoi infection (153).

Finally, Miller and coworkers (154, 155) recently demonstrated an unexpected inhibition of TLR4-dependent inflammatory cytokine expression by the CLR Dectin-1 and Mincle (Fig. 4C). First, they observed that Dectin-1–deficient mice showed more hepatic fibrosis in a model of liver inflammation (154). Similarly, Mincle-deficient mice were more susceptible to endotoxic shock than were wild-type controls, resulting in higher mortality and elevated cytokine levels (155). In both studies, this enhanced susceptibility was attributed to increased levels of the TLR4 coreceptor CD14 in Dectin-1– or Mincle-deficient mice. Blockade of PKC and M-CSF abrogated the elevated CD14 expression in Dectin-1–deficient mice (154). Mincle deletion led to enhanced JNK phosphorylation but decreased p38 phosphorylation and subsequent activation of Socs1, A20, and ABIN3, which supposedly control CD14 expression, and in addition may induce degradation of Traf6 and MyD88 (155). These findings suggest that control of TLR responses by CLRs cannot only occur by transcriptional control but also by (indirect) modulation of the levels of components of the TLR signaling machinery. The nature of the ligands for Dectin-1 and Mincle in the hepatic fibrosis and LPS challenge models has not been defined. However, in the case of Mincle, the same group most recently demonstrated evidence that the endogenous Mincle ligand SAP130 (6) triggers Mincle in a mouse pancreatic tumor model, promoting tumor growth through inhibitory effects on T cell responses (156), and in a mouse model of acute liver inflammation, exacerbating disease (157). SAP130 may be induced and released during LPS- or infection-induced inflammation from dying cells and provide the trigger for inhibitory Mincle signaling.

CLRs as a group of PRRs have gained increasing attention during the last 10 y, with Dectin-1 often regarded as a prototypic receptor. Similar to Dectin-1, the related receptors Dectin-2, Mincle, and Mcl were found to signal dependent on the Syk/Card9 pathway. These CLRs have been characterized as receptors not only for various pathogens but also endogenous ligands. Consequently, their roles reach from infection and inflammatory conditions to homeostatic regulation. The number of pathways and signaling events identified downstream of CLR ligation are continuously increasing, providing us with a gradually more precise but also more complex picture of signal transduction and reprogramming triggered in innate immune cells. Further research is needed to clarify which of these pathways are universal, such as the Syk/Card9 axis, and which responses occur in certain species, certain cell types, or for certain receptors or ligands. Pathogens are recognized by multiple PRRs simultaneously, and therefore it is essential to investigate not only events dependent on a single receptor but also crosstalk between receptors or even classes of receptors. We have reviewed studies investigating the integration of signals derived from CLRs and TLRs, with examples for both synergistic and antagonistic interactions between different CLRs or with TLRs. Although there are many examples of collaborative signaling with strongly boosted responses, for example, by concurrent stimulation of TLR2 and Dectin-1, accumulating evidence shows that specific CLR signaling can attenuate or abrogate at least certain types of CLR/TLR-induced activation. Another important aspect of CLR research has been the cross-regulation of expression levels at the mRNA and protein levels, which can determine the level of responsiveness to the respective microbial ligands. A fascinating question for future research in this area will be to investigate the consequences of direct receptor interaction, such as formation of Mcl–Dectin-2/Mincle heterodimers, on the avidity and specificity of ligand binding. Thus, signaling crosstalk downstream of CLRs specifically modulates immune reactions and can control inflammatory responses. Mapping this complex signaling network will result in a new level of understanding of the role of CLRs in innate and adaptive immune responses and may open up perspectives to target these receptors for treatment and prevention of infectious and inflammatory conditions.

This work was supported by Research Council of Norway Centers of Excellence Grant 223255/F50 (to J.O.) and German Research Foundation Grants RTG1660, TP-A2 and CRC796, TP-B6 (to R.L.).

Abbreviations used in this article:

CLR

C-type lectin receptor

CR3

complement receptor 3

CTLD

C-type lectin domain

DC

dendritic cell

Dectin

dendritic cell–associated C-type lectin

IRAK

IL-1R–associated kinase

IRF

IFN regulatory factor

iNOS

inducible NO synthase

Mcl

macrophage C-type lectin

Mincle

macrophage-inducible C-type lectin

PAMP

pathogen-associated molecular pattern

PKC

protein kinase C

PLC

phospholipase C

PRR

pattern recognition receptor

ROS

reactive oxygen species

SOCS

suppressor of cytokine signaling

Syk

spleen tyrosine kinase

TDB

trehalose dibehenate

TDM

trehalose dimycolate

TIR

Toll/IL-1R

TRIF

Toll/IL-1R domain–containing adapter inducing IFN-β.

1
Yokoyama
W. M.
,
Ryan
J. C.
,
Hunter
J. J.
,
Smith
H. R.
,
Stark
M.
,
Seaman
W. E.
.
1991
.
cDNA cloning of mouse NKR-P1 and genetic linkage with LY-49. Identification of a natural killer cell gene complex on mouse chromosome 6.
J. Immunol.
147
:
3229
3236
.
2
Sobanov
Y.
,
Bernreiter
A.
,
Derdak
S.
,
Mechtcheriakova
D.
,
Schweighofer
B.
,
Düchler
M.
,
Kalthoff
F.
,
Hofer
E.
.
2001
.
A novel cluster of lectin-like receptor genes expressed in monocytic, dendritic and endothelial cells maps close to the NK receptor genes in the human NK gene complex.
Eur. J. Immunol.
31
:
3493
3503
.
3
Ariizumi
K.
,
Shen
G.-L.
,
Shikano
S.
,
Ritter
R.
 III
,
Zukas
P.
,
Edelbaum
D.
,
Morita
A.
,
Takashima
A.
.
2000
.
Cloning of a second dendritic cell-associated C-type lectin (dectin-2) and its alternatively spliced isoforms.
J. Biol. Chem.
275
:
11957
11963
.
4
Sancho
D.
,
Reis e Sousa
C.
.
2012
.
Signaling by myeloid C-type lectin receptors in immunity and homeostasis.
Annu. Rev. Immunol.
30
:
491
529
.
5
Dambuza
I. M.
,
Brown
G. D.
.
2015
.
C-type lectins in immunity: recent developments.
Curr. Opin. Immunol.
32
:
21
27
.
6
Yamasaki
S.
,
Ishikawa
E.
,
Sakuma
M.
,
Hara
H.
,
Ogata
K.
,
Saito
T.
.
2008
.
Mincle is an ITAM-coupled activating receptor that senses damaged cells.
Nat. Immunol.
9
:
1179
1188
.
7
Suzuki
Y.
,
Nakano
Y.
,
Mishiro
K.
,
Takagi
T.
,
Tsuruma
K.
,
Nakamura
M.
,
Yoshimura
S.
,
Shimazawa
M.
,
Hara
H.
.
2013
.
Involvement of mincle and Syk in the changes to innate immunity after ischemic stroke.
Sci. Rep.
3
:
3177
.
8
de Rivero Vaccari
J. C.
,
Brand
F. J.
 III
,
Berti
A. F.
,
Alonso
O. F.
,
Bullock
M. R.
,
de Rivero Vaccari
J. P.
.
2015
.
Mincle signaling in the innate immune response after traumatic brain injury.
J. Neurotrauma
32
:
228
236
.
9
Arumugam
T. V.
,
Manzanero
S.
,
Furtado
M.
,
Biggins
P. J.
,
Hsieh
Y.-H.
,
Gelderblom
M.
,
MacDonald
K. P. A.
,
Salimova
E.
,
Li
Y.-I.
,
Korn
O.
, et al
.
2016
.
An atypical role for the myeloid receptor mincle in central nervous system injury.
J. Cereb. Blood Flow Metab.
DOI: 10.1177/0271678X16661201
.
10
Iliev
I. D.
,
Funari
V. A.
,
Taylor
K. D.
,
Nguyen
Q.
,
Reyes
C. N.
,
Strom
S. P.
,
Brown
J.
,
Becker
C. A.
,
Fleshner
P. R.
,
Dubinsky
M.
, et al
.
2012
.
Interactions between commensal fungi and the C-type lectin receptor dectin-1 influence colitis.
Science
336
:
1314
1317
.
11
Underhill
D. M.
,
Iliev
I. D.
.
2014
.
The mycobiota: interactions between commensal fungi and the host immune system.
Nat. Rev. Immunol.
14
:
405
416
.
12
Wang
T.
,
Pan
D.
,
Zhou
Z.
,
You
Y.
,
Jiang
C.
,
Zhao
X.
,
Lin
X.
.
2016
.
Dectin-3 deficiency promotes colitis development due to impaired antifungal innate immune responses in the gut.
PLoS Pathog.
12
:
e1005662
.
13
Geijtenbeek
T. B. H.
,
Gringhuis
S. I.
.
2016
.
C-type lectin receptors in the control of T helper cell differentiation.
Nat. Rev. Immunol.
16
:
433
448
.
14
Lang
R.
,
Schoenen
H.
,
Desel
C.
.
2011
.
Targeting Syk-Card9-activating C-type lectin receptors by vaccine adjuvants: findings, implications and open questions.
Immunobiology
216
:
1184
1191
.
15
Johannssen
T.
,
Lepenies
B.
.
2015
.
Identification and characterization of carbohydrate-based adjuvants.
Methods Mol. Biol.
1331
:
173
187
.
16
Thaiss
C. A.
,
Levy
M.
,
Itav
S.
,
Elinav
E.
.
2016
.
Integration of innate immune signaling.
Trends Immunol.
37
:
84
101
.
17
Gay
N. J.
,
Symmons
M. F.
,
Gangloff
M.
,
Bryant
C. E.
.
2014
.
Assembly and localization of Toll-like receptor signalling complexes.
Nat. Rev. Immunol.
14
:
546
558
.
18
Bagchi
A.
,
Herrup
E. A.
,
Warren
H. S.
,
Trigilio
J.
,
Shin
H. S.
,
Valentine
C.
,
Hellman
J.
.
2007
.
MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists.
J. Immunol.
178
:
1164
1171
.
19
Trinchieri
G.
,
Sher
A.
.
2007
.
Cooperation of Toll-like receptor signals in innate immune defence.
Nat. Rev. Immunol.
7
:
179
190
.
20
Zelensky
A. N.
,
Gready
J. E.
.
2005
.
The C-type lectin-like domain superfamily.
FEBS J.
272
:
6179
6217
.
21
Drickamer
K.
1999
.
C-type lectin-like domains.
Curr. Opin. Struct. Biol.
9
:
585
590
.
22
Öhman
T.
,
Teirilä
L.
,
Lahesmaa-Korpinen
A. M.
,
Cypryk
W.
,
Veckman
V.
,
Saijo
S.
,
Wolff
H.
,
Hautaniemi
S.
,
Nyman
T. A.
,
Matikainen
S.
.
2014
.
Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages.
J. Immunol.
192
:
5952
5962
.
23
Cardone
M.
,
Dzutsev
A. K.
,
Li
H.
,
Riteau
N.
,
Gerosa
F.
,
Shenderov
K.
,
Winkler-Pickett
R.
,
Provezza
L.
,
Riboldi
E.
,
Leighty
R. M.
, et al
.
2014
.
Interleukin-1 and interferon-γ orchestrate β-glucan-activated human dendritic cell programming via IκB-ζ modulation.
PLoS One
9
:
e114516
.
24
Werninghaus
K.
,
Babiak
A.
,
Gross
O.
,
Hölscher
C.
,
Dietrich
H.
,
Agger
E. M.
,
Mages
J.
,
Mocsai
A.
,
Schoenen
H.
,
Finger
K.
, et al
.
2009
.
Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ-Syk-Card9-dependent innate immune activation.
J. Exp. Med.
206
:
89
97
.
25
Lee
E. J.
,
Brown
B. R.
,
Vance
E. E.
,
Snow
P. E.
,
Silver
P. B.
,
Heinrichs
D.
,
Lin
X.
,
Iwakura
Y.
,
Wells
C. A.
,
Caspi
R. R.
,
Rosenzweig
H. L.
.
2016
.
Mincle activation and the Syk/Card9 signaling axis are central to the development of autoimmune disease of the eye.
J. Immunol.
196
:
3148
3158
.
26
LeibundGut-Landmann
S.
,
Gross
O.
,
Robinson
M. J.
,
Osorio
F.
,
Slack
E. C.
,
Tsoni
S. V.
,
Schweighoffer
E.
,
Tybulewicz
V.
,
Brown
G. D.
,
Ruland
J.
,
Reis e Sousa
C.
.
2007
.
Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.
Nat. Immunol.
8
:
630
638
.
27
Gerosa
F.
,
Baldani-Guerra
B.
,
Lyakh
L. A.
,
Batoni
G.
,
Esin
S.
,
Winkler-Pickett
R. T.
,
Consolaro
M. R.
,
De Marchi
M.
,
Giachino
D.
,
Robbiano
A.
, et al
.
2008
.
Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells.
J. Exp. Med.
205
:
1447
1461
.
28
Plato
A.
,
Willment
J. A.
,
Brown
G. D.
.
2013
.
C-type lectin-like receptors of the dectin-1 cluster: ligands and signaling pathways.
Int. Rev. Immunol.
32
:
134
156
.
29
Reid
D. M.
,
Gow
N. A. R.
,
Brown
G. D.
.
2009
.
Pattern recognition: recent insights from dectin-1.
Curr. Opin. Immunol.
21
:
30
37
.
30
Willment
J. A.
,
Gordon
S.
,
Brown
G. D.
.
2001
.
Characterization of the human β-glucan receptor and its alternatively spliced isoforms.
J. Biol. Chem.
276
:
43818
43823
.
31
Brown
G. D.
,
Gordon
S.
.
2001
.
Immune recognition. A new receptor for β-glucans.
Nature
413
:
36
37
.
32
Adachi
Y.
,
Ishii
T.
,
Ikeda
Y.
,
Hoshino
A.
,
Tamura
H.
,
Aketagawa
J.
,
Tanaka
S.
,
Ohno
N.
.
2004
.
Characterization of beta-glucan recognition site on C-type lectin, dectin 1.
Infect. Immun.
72
:
4159
4171
.
33
Yadav
M.
,
Schorey
J. S.
.
2006
.
The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria.
Blood
108
:
3168
3175
.
34
Brown
J.
,
O’Callaghan
C. A.
,
Marshall
A. S. J.
,
Gilbert
R. J. C.
,
Siebold
C.
,
Gordon
S.
,
Brown
G. D.
,
Jones
E. Y.
.
2007
.
Structure of the fungal β-glucan-binding immune receptor dectin-1: implications for function.
Protein Sci.
16
:
1042
1052
.
35
Goodridge
H. S.
,
Reyes
C. N.
,
Becker
C. A.
,
Katsumoto
T. R.
,
Ma
J.
,
Wolf
A. J.
,
Bose
N.
,
Chan
A. S. H.
,
Magee
A. S.
,
Danielson
M. E.
, et al
.
2011
.
Activation of the innate immune receptor dectin-1 upon formation of a “phagocytic synapse”.
Nature
472
:
471
475
.
36
Fuller
G. L.
,
Williams
J. A.
,
Tomlinson
M. G.
,
Eble
J. A.
,
Hanna
S. L.
,
Pöhlmann
S.
,
Suzuki-Inoue
K.
,
Ozaki
Y.
,
Watson
S. P.
,
Pearce
A. C.
.
2007
.
The C-type lectin receptors CLEC-2 and dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade.
J. Biol. Chem.
282
:
12397
12409
.
37
Rogers
N. C.
,
Slack
E. C.
,
Edwards
A. D.
,
Nolte
M. A.
,
Schulz
O.
,
Schweighoffer
E.
,
Williams
D. L.
,
Gordon
S.
,
Tybulewicz
V. L.
,
Brown
G. D.
,
Reis e Sousa
C.
.
2005
.
Syk-dependent cytokine induction by dectin-1 reveals a novel pattern recognition pathway for C type lectins.
Immunity
22
:
507
517
.
38
Deng
Z.
,
Ma
S.
,
Zhou
H.
,
Zang
A.
,
Fang
Y.
,
Li
T.
,
Shi
H.
,
Liu
M.
,
Du
M.
,
Taylor
P. R.
, et al
.
2015
.
Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses.
Nat. Immunol.
16
:
642
652
.
39
Xu
S.
,
Huo
J.
,
Lee
K.-G.
,
Kurosaki
T.
,
Lam
K.-P.
.
2009
.
Phospholipase Cγ2 is critical for dectin-1-mediated Ca2+ flux and cytokine production in dendritic cells.
J. Biol. Chem.
284
:
7038
7046
.
40
Huang
J.-H.
,
Lin
C.Y.
,
Wu
S.Y.
,
Chen
W.Y.
,
Chu
C.L.
,
Brown
G. D.
,
Chuu
C.P.
,
Wu-Hsieh
B. A.
.
2015
.
CR3 and dectin-1 collaborate in macrophage cytokine response through association on lipid rafts and activation of Syk-JNK-AP-1 pathway.
PLoS Pathog.
11
:
e1004985
.
41
Elsori
D. H.
,
Yakubenko
V. P.
,
Roome
T.
,
Thiagarajan
P. S.
,
Bhattacharjee
A.
,
Yadav
S. P.
,
Cathcart
M. K.
.
2011
.
Protein kinase Cδ is a critical component of dectin-1 signaling in primary human monocytes.
J. Leukoc. Biol.
90
:
599
611
.
42
Strasser
D.
,
Neumann
K.
,
Bergmann
H.
,
Marakalala
M. J.
,
Guler
R.
,
Rojowska
A.
,
Hopfner
K. P.
,
Brombacher
F.
,
Urlaub
H.
,
Baier
G.
, et al
.
2012
.
Syk kinase-coupled C-type lectin receptors engage protein kinase C-σ to elicit Card9 adaptor-mediated innate immunity.
Immunity
36
:
32
42
.
43
Gross
O.
,
Gewies
A.
,
Finger
K.
,
Schäfer
M.
,
Sparwasser
T.
,
Peschel
C.
,
Förster
I.
,
Ruland
J.
.
2006
.
Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity.
Nature
442
:
651
656
.
44
Roth
S.
,
Ruland
J.
.
2013
.
Caspase recruitment domain-containing protein 9 signaling in innate immunity and inflammation.
Trends Immunol.
34
:
243
250
.
45
Cao
Z.
,
Conway
K. L.
,
Heath
R. J.
,
Rush
J. S.
,
Leshchiner
E. S.
,
Ramirez-Ortiz
Z. G.
,
Nedelsky
N. B.
,
Huang
H.
,
Ng
A.
,
Gardet
A.
, et al
.
2015
.
Ubiquitin ligase TRIM62 regulates CARD9-mediated anti-fungal immunity and intestinal inflammation.
Immunity
43
:
715
726
.
46
Geijtenbeek
T. B.
,
Gringhuis
S. I.
.
2009
.
Signalling through C-type lectin receptors: shaping immune responses.
Nat. Rev. Immunol.
9
:
465
479
.
47
Lemoine
S.
,
Jaron
B.
,
Tabka
S.
,
Ettreiki
C.
,
Deriaud
E.
,
Zhivaki
D.
,
Le Ray
C.
,
Launay
O.
,
Majlessi
L.
,
Tissieres
P.
, et al
.
2015
.
Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells.
J. Allergy Clin. Immunol.
136
:
1355
1368.e1–15
.
48
Gringhuis
S. I.
,
den Dunnen
J.
,
Litjens
M.
,
van der Vlist
M.
,
Wevers
B.
,
Bruijns
S. C. M.
,
Geijtenbeek
T. B. H.
.
2009
.
Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk.
Nat. Immunol.
10
:
203
213
.
49
Ifrim
D. C.
,
Joosten
L. A.
,
Kullberg
B. J.
,
Jacobs
L.
,
Jansen
T.
,
Williams
D. L.
,
Gow
N. A.
,
van der Meer
J. W.
,
Netea
M. G.
,
Quintin
J.
.
2013
.
Candida albicans primes TLR cytokine responses through a dectin-1/Raf-1-mediated pathway.
J. Immunol.
190
:
4129
4135
.
50
Wevers
B. A.
,
Kaptein
T. M.
,
Zijlstra-Willems
E. M.
,
Theelen
B.
,
Boekhout
T.
,
Geijtenbeek
T. B.
,
Gringhuis
S. I.
.
2014
.
Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity.
Cell Host Microbe
15
:
494
505
.
51
del Fresno
C.
,
Soulat
D.
,
Roth
S.
,
Blazek
K.
,
Udalova
I.
,
Sancho
D.
,
Ruland
J.
,
Ardavín
C.
.
2013
.
Interferon-β production via dectin-1-Syk-IRF5 signaling in dendritic cells is crucial for immunity to C. albicans.
Immunity
38
:
1176
1186
.
52
Eberle
M. E.
,
Dalpke
A. H.
.
2012
.
Dectin-1 stimulation induces suppressor of cytokine signaling 1, thereby modulating TLR signaling and T cell responses.
J. Immunol.
188
:
5644
5654
.
53
Slack
E. C.
,
Robinson
M. J.
,
Hernanz-Falcón
P.
,
Brown
G. D.
,
Williams
D. L.
,
Schweighoffer
E.
,
Tybulewicz
V. L.
,
Reis e Sousa
C.
.
2007
.
Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan.
Eur. J. Immunol.
37
:
1600
1612
.
54
Jia
X. M.
,
Tang
B.
,
Zhu
L. L.
,
Liu
Y. H.
,
Zhao
X. Q.
,
Gorjestani
S.
,
Hsu
Y. M. S.
,
Yang
L.
,
Guan
J. H.
,
Xu
G. T.
,
Lin
X.
.
2014
.
CARD9 mediates dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity.
J. Exp. Med.
211
:
2307
2321
.
55
Ma
J.
,
Becker
C.
,
Lowell
C. A.
,
Underhill
D. M.
.
2012
.
Dectin-1-triggered recruitment of light chain 3 protein to phagosomes facilitates major histocompatibility complex class II presentation of fungal-derived antigens.
J. Biol. Chem.
287
:
34149
34156
.
56
Underhill
D. M.
,
Rossnagle
E.
,
Lowell
C. A.
,
Simmons
R. M.
.
2005
.
Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production.
Blood
106
:
2543
2550
.
57
Gross
O.
,
Poeck
H.
,
Bscheider
M.
,
Dostert
C.
,
Hannesschläger
N.
,
Endres
S.
,
Hartmann
G.
,
Tardivel
A.
,
Schweighoffer
E.
,
Tybulewicz
V.
, et al
.
2009
.
Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.
Nature
459
:
433
436
.
58
van de Veerdonk
F. L.
,
Teirlinck
A. C.
,
Kleinnijenhuis
J.
,
Kullberg
B. J.
,
van Crevel
R.
,
van der Meer
J. W.
,
Joosten
L. A.
,
Netea
M. G.
.
2010
.
Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1.
J. Leukoc. Biol.
88
:
227
232
.
59
Zwolanek
F.
,
Riedelberger
M.
,
Stolz
V.
,
Jenull
S.
,
Istel
F.
,
Köprülü
A. D.
,
Ellmeier
W.
,
Kuchler
K.
.
2014
.
The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome.
PLoS Pathog.
10
:
e1004525
.
60
Gringhuis
S. I.
,
Kaptein
T. M.
,
Wevers
B. A.
,
Theelen
B.
,
van der Vlist
M.
,
Boekhout
T.
,
Geijtenbeek
T. B.
.
2012
.
Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome.
Nat. Immunol.
13
:
246
254
.
61
Ganesan
S.
,
Rathinam
V. A. K.
,
Bossaller
L.
,
Army
K.
,
Kaiser
W. J.
,
Mocarski
E. S.
,
Dillon
C. P.
,
Green
D. R.
,
Mayadas
T. N.
,
Levitz
S. M.
, et al
.
2014
.
Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1β production in response to β-glucans and the fungal pathogen, Candida albicans.
J. Immunol.
193
:
2519
2530
.
62
Goodridge
H. S.
,
Simmons
R. M.
,
Underhill
D. M.
.
2007
.
Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells.
J. Immunol
.
178
:
3107
3115
.
63
Zelante
T.
,
Wong
A. Y. W.
,
Mencarelli
A.
,
Foo
S.
,
Zolezzi
F.
,
Lee
B.
,
Poidinger
M.
,
Ricciardi-Castagnoli
P.
,
Fric
J.
.
2016
.
Impaired calcineurin signaling in myeloid cells results in downregulation of pentraxin-3 and increased susceptibility to aspergillosis.
Mucosal Immunol
.
doi:10.1038/mi.2016.52
.
64
Matsumoto
M.
,
Tanaka
T.
,
Kaisho
T.
,
Sanjo
H.
,
Copeland
N. G.
,
Gilbert
D. J.
,
Jenkins
N. A.
,
Akira
S.
.
1999
.
A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages
.
J. Immunol.
163
:
5039
5048
.
65
Balch
S. G.
,
Greaves
D. R.
,
Gordon
S.
,
McKnight
A. J.
.
2002
.
Organization of the mouse macrophage C-type lectin (Mcl) gene and identification of a subgroup of related lectin molecules.
Eur. J. Immunogenet.
29
:
61
64
.
66
Arce
I.
,
Martínez-Muñoz
L.
,
Roda-Navarro
P.
,
Fernández-Ruiz
E.
.
2004
.
The human C-type lectin CLECSF8 is a novel monocyte/macrophage endocytic receptor.
Eur. J. Immunol.
34
:
210
220
.
67
Miyake
Y.
,
Toyonaga
K.
,
Mori
D.
,
Kakuta
S.
,
Hoshino
Y.
,
Oyamada
A.
,
Yamada
H.
,
Ono
K.
,
Suyama
M.
,
Iwakura
Y.
, et al
.
2013
.
C-type lectin MCL is an FcRγ-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor.
Immunity
38
:
1050
1062
.
68
Sato
K.
,
Yang
X. L.
,
Yudate
T.
,
Chung
J. S.
,
Wu
J.
,
Luby-Phelps
K.
,
Kimberly
R. P.
,
Underhill
D.
,
Cruz
P. D.
 Jr.
,
Ariizumi
K.
.
2006
.
Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor γ chain to induce innate immune responses.
J. Biol. Chem.
281
:
38854
38866
.
69
Kerscher
B.
,
Willment
J. A.
,
Brown
G. D.
.
2013
.
The Dectin-2 family of C-type lectin-like receptors: an update.
Int. Immunol.
25
:
271
277
.
70
Furukawa
A.
,
Kamishikiryo
J.
,
Mori
D.
,
Toyonaga
K.
,
Okabe
Y.
,
Toji
A.
,
Kanda
R.
,
Miyake
Y.
,
Ose
T.
,
Yamasaki
S.
,
Maenaka
K.
.
2013
.
Structural analysis for glycolipid recognition by the C-type lectins mincle and MCL.
Proc. Natl. Acad. Sci. USA
110
:
17438
17443
.
71
Feinberg
H.
,
Jégouzo
S. A.
,
Rowntree
T. J.
,
Guan
Y.
,
Brash
M. A.
,
Taylor
M. E.
,
Weis
W. I.
,
Drickamer
K.
.
2013
.
Mechanism for recognition of an unusual mycobacterial glycolipid by the macrophage receptor mincle.
J. Biol. Chem.
288
:
28457
28465
.
72
Jégouzo
S. A.
,
Harding
E. C.
,
Acton
O.
,
Rex
M. J.
,
Fadden
A. J.
,
Taylor
M. E.
,
Drickamer
K.
.
2014
.
Defining the conformation of human mincle that interacts with mycobacterial trehalose dimycolate.
Glycobiology
24
:
1291
1300
.
73
Rambaruth
N. D.
,
Jégouzo
S. A.
,
Marlor
H.
,
Taylor
M. E.
,
Drickamer
K.
.
2015
.
Mouse mincle: characterization as a model for human mincle and evolutionary implications.
Molecules
20
:
6670
6682
.
74
Feinberg
H.
,
Rambaruth
N. D.
,
Jégouzo
S. A.
,
Jacobsen
K. M.
,
Djurhuus
R.
,
Poulsen
T. B.
,
Weis
W. I.
,
Taylor
M. E.
,
Drickamer
K.
.
2016
.
Binding sites for acylated trehalose analogs of glycolipid ligands on an extended carbohydrate-recognition domain of the macrophage receptor Mincle.
J. Biol. Chem.
291
:
21222
21233
.
75
Richardson
M. B.
,
Williams
S. J.
.
2014
.
MCL and Mincle: C-type lectin receptors that sense damaged self and pathogen-associated molecular patterns.
Front. Immunol.
5
:
288
.
76
Smith
D. G.
,
Williams
S. J.
.
2016
.
Immune sensing of microbial glycolipids and related conjugates by T cells and the pattern recognition receptors MCL and Mincle.
Carbohydr. Res.
420
:
32
45
.
77
Drickamer
K.
,
Taylor
M. E.
.
2015
.
Recent insights into structures and functions of C-type lectins in the immune system.
Curr. Opin. Struct. Biol.
34
:
26
34
.
78
Agger
E. M.
,
Rosenkrands
I.
,
Hansen
J.
,
Brahimi
K.
,
Vandahl
B. S.
,
Aagaard
C.
,
Werninghaus
K.
,
Kirschning
C.
,
Lang
R.
,
Christensen
D.
, et al
.
2008
.
Cationic liposomes formulated with synthetic mycobacterial cordfactor (CAF01): a versatile adjuvant for vaccines with different immunological requirements.
PLoS One
3
:
e3116
.
79
Román
V. R.
,
Jensen
K. J.
,
Jensen
S. S.
,
Leo-Hansen
C.
,
Jespersen
S.
,
da Silva Té
D.
,
Rodrigues
C. M.
,
Janitzek
C. M.
,
Vinner
L.
,
Katzenstein
T. L.
, et al
.
2013
.
Therapeutic vaccination using cationic liposome-adjuvanted HIV type 1 peptides representing HLA-supertype-restricted subdominant T cell epitopes: safety, immunogenicity, and feasibility in Guinea-Bissau.
AIDS Res. Hum. Retroviruses
29
:
1504
1512
.
80
van Dissel
J. T.
,
Joosten
S. A.
,
Hoff
S. T.
,
Soonawala
D.
,
Prins
C.
,
Hokey
D. A.
,
O’Dee
D. M.
,
Graves
A.
,
Thierry-Carstensen
B.
,
Andreasen
L. V.
, et al
.
2014
.
A novel liposomal adjuvant system, CAF01, promotes long-lived Mycobacterium tuberculosis-specific T-cell responses in human.
Vaccine
32
:
7098
7107
.
81
van der Peet
P. L.
,
Gunawan
C.
,
Torigoe
S.
,
Yamasaki
S.
,
Williams
S. J.
.
2015
.
Corynomycolic acid-containing glycolipids signal through the pattern recognition receptor mincle.
Chem. Commun. (Camb.)
51
:
5100
5103
.
82
Stocker
B. L.
,
Khan
A. A.
,
Chee
S. H.
,
Kamena
F.
,
Timmer
M. S.
.
2014
.
On one leg: trehalose monoesters activate macrophages in a Mincle-dependant manner.
ChemBioChem
15
:
382
388
.
83
Jacobsen
K. M.
,
Keiding
U. B.
,
Clement
L. L.
,
Schaffert
E. S.
,
Rambaruth
N. D.
,
Johannsen
M.
,
Drickamer
K.
,
Poulsen
T. B.
.
2015
.
The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle.
MedChemComm
6
:
647
652
.
84
Huber
A.
,
Kallerup
R. S.
,
Korsholm
K. S.
,
Franzyk
H.
,
Lepenies
B.
,
Christensen
D.
,
Foged
C.
,
Lang
R.
.
2016
.
Trehalose diester glycolipids are superior to the monoesters in binding to Mincle, activation of macrophages in vitro and adjuvant activity in vivo.
Innate Immun.
22
:
405
418
.
85
Hattori
Y.
,
Morita
D.
,
Fujiwara
N.
,
Mori
D.
,
Nakamura
T.
,
Harashima
H.
,
Yamasaki
S.
,
Sugita
M.
.
2014
.
Glycerol monomycolate is a novel ligand for the human, but not mouse macrophage inducible C-type lectin, Mincle.
J. Biol. Chem.
289
:
15405
15412
.
86
Kiyotake
R.
,
Oh-Hora
M.
,
Ishikawa
E.
,
Miyamoto
T.
,
Ishibashi
T.
,
Yamasaki
S.
.
2015
.
Human Mincle binds to cholesterol crystals and triggers innate immune responses.
J. Biol. Chem.
290
:
25322
.
87
Toyonaga
K.
,
Miyake
Y.
,
Yamasaki
S.
.
2014
.
Characterization of the receptors for mycobacterial cord factor in Guinea pig.
PLoS One
9
:
e88747
e88747
.
88
Behler
F.
,
Steinwede
K.
,
Balboa
L.
,
Ueberberg
B.
,
Maus
R.
,
Kirchhof
G.
,
Yamasaki
S.
,
Welte
T.
,
Maus
U. A.
.
2012
.
Role of Mincle in alveolar macrophage-dependent innate immunity against mycobacterial infections in mice.
J. Immunol.
189
:
3121
3129
.
89
Behler
F.
,
Maus
R.
,
Bohling
J.
,
Knippenberg
S.
,
Kirchhof
G.
,
Nagata
M.
,
Jonigk
D.
,
Izykowski
N.
,
Mägel
L.
,
Welte
T.
, et al
.
2015
.
Macrophage-inducible C-type lectin mincle-expressing dendritic cells contribute to control of splenic Mycobacterium bovis BCG infection in mice.
Infect. Immun.
83
:
184
196
.
90
Heitmann
L.
,
Schoenen
H.
,
Ehlers
S.
,
Lang
R.
,
Hölscher
C.
.
2013
.
Mincle is not essential for controlling Mycobacterium tuberculosis infection.
Immunobiology
218
:
506
516
.
91
Wilson
G. J.
,
Marakalala
M. J.
,
Hoving
J. C.
,
van Laarhoven
A.
,
Drummond
R. A.
,
Kerscher
B.
,
Keeton
R.
,
van de Vosse
E.
,
Ottenhoff
T. H.
,
Plantinga
T. S.
, et al
.
2015
.
The C-type lectin receptor CLECSF8/CLEC4D is a key component of anti-mycobacterial immunity.
Cell Host Microbe
17
:
252
259
.
92
Graham
L. M.
,
Gupta
V.
,
Schafer
G.
,
Reid
D. M.
,
Kimberg
M.
,
Dennehy
K. M.
,
Hornsell
W. G.
,
Guler
R.
,
Campanero-Rhodes
M. A.
,
Palma
A. S.
, et al
.
2012
.
The C-type lectin receptor CLECSF8 (CLEC4D) is expressed by myeloid cells and triggers cellular activation through Syk kinase.
J. Biol. Chem.
287
:
25964
25974
.
93
Zhu
L.-L.
,
Zhao
X.-Q.
,
Jiang
C.
,
You
Y.
,
Chen
X.-P.
,
Jiang
Y.-Y.
,
Jia
X.-M.
,
Lin
X.
.
2013
.
C-type lectin receptors dectin-3 and dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection.
Immunity
39
:
324
334
.
94
Wang
H.
,
Li
M.
,
Lerksuthirat
T.
,
Klein
B.
,
Wüthrich
M.
.
2015
.
The C-type lectin receptor MCL mediates vaccine-induced immunity against infection with Blastomyces dermatitidiss.
Infect. Immun.
84
:
635
642
.
95
Dorhoi
A.
,
Desel
C.
,
Yeremeev
V.
,
Pradl
L.
,
Brinkmann
V.
,
Mollenkopf
H. J.
,
Hanke
K.
,
Gross
O.
,
Ruland
J.
,
Kaufmann
S. H.
.
2010
.
The adaptor molecule CARD9 is essential for tuberculosis control.
J. Exp. Med.
207
:
777
792
.
96
Kodar
K.
,
Eising
S.
,
Khan
A. A.
,
Steiger
S.
,
Harper
J. L.
,
Timmer
M. S.
,
Stocker
B. L.
.
2015
.
The uptake of trehalose glycolipids by macrophages is independent of Mincle.
ChemBioChem
16
:
683
693
.
97
Ishikawa
E.
,
Ishikawa
T.
,
Morita
Y. S.
,
Toyonaga
K.
,
Yamada
H.
,
Takeuchi
O.
,
Kinoshita
T.
,
Akira
S.
,
Yoshikai
Y.
,
Yamasaki
S.
.
2009
.
Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin mincle.
J. Exp. Med.
206
:
2879
2888
.
98
Schoenen
H.
,
Bodendorfer
B.
,
Hitchens
K.
,
Manzanero
S.
,
Werninghaus
K.
,
Nimmerjahn
F.
,
Agger
E. M.
,
Stenger
S.
,
Andersen
P.
,
Ruland
J.
, et al
.
2010
.
Cutting edge: mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate.
J. Immunol.
184
:
2756
2760
.
99
Saijo
S.
,
Ikeda
S.
,
Yamabe
K.
,
Kakuta
S.
,
Ishigame
H.
,
Akitsu
A.
,
Fujikado
N.
,
Kusaka
T.
,
Kubo
S.
,
Chung
S. H.
, et al
.
2010
.
Dectin-2 recognition of α-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans.
Immunity
32
:
681
691
.
100
Gorjestani
S.
,
Yu
M.
,
Tang
B.
,
Zhang
D.
,
Wang
D.
,
Lin
X.
.
2011
.
Phospholipase Cγ2 (PLCγ2) is key component in dectin-2 signaling pathway, mediating anti-fungal innate immune responses.
J. Biol. Chem.
286
:
43651
43659
.
101
Gringhuis
S. I.
,
Wevers
B. A.
,
Kaptein
T. M.
,
van Capel
T. M.
,
Theelen
B.
,
Boekhout
T.
,
de Jong
E. C.
,
Geijtenbeek
T. B.
.
2011
.
Selective C-Rel activation via Malt1 controls anti-fungal TH-17 immunity by dectin-1 and dectin-2.
PLoS Pathog.
7
:
e1001259
.
102
Robinson
M. J.
,
Osorio
F.
,
Rosas
M.
,
Freitas
R. P.
,
Schweighoffer
E.
,
Gross
O.
,
Verbeek
J. S.
,
Ruland
J.
,
Tybulewicz
V.
,
Brown
G. D.
, et al
.
2009
.
Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection.
J. Exp. Med.
206
:
2037
2051
.
103
Bi
L.
,
Gojestani
S.
,
Wu
W.
,
Hsu
Y. M.
,
Zhu
J.
,
Ariizumi
K.
,
Lin
X.
.
2010
.
CARD9 mediates dectin-2-induced IαBα kinase ubiquitination leading to activation of NF-κB in response to stimulation by the hyphal form of Candida albicans.
J. Biol. Chem.
285
:
25969
25977
.
104
Schoenen
H.
,
Huber
A.
,
Sonda
N.
,
Zimmermann
S.
,
Jantsch
J.
,
Lepenies
B.
,
Bronte
V.
,
Lang
R.
.
2014
.
Differential control of Mincle-dependent cord factor recognition and macrophage responses by the transcription factors C/EBPβ and HIF1α.
J. Immunol.
193
:
3664
3675
.
105
Lee
W.B.
,
Kang
J.S.
,
Yan
J.J.
,
Lee
M. S.
,
Jeon
B.Y.
,
Cho
S.N.
,
Kim
Y.J.
.
2012
.
Neutrophils promote mycobacterial trehalose dimycolate-induced lung inflammation via the mincle pathway.
PLoS Pathog.
8
:
e1002614
.
106
Lee
M. J.
,
Yoshimoto
E.
,
Saijo
S.
,
Iwakura
Y.
,
Lin
X.
,
Katz
H. R.
,
Kanaoka
Y.
,
Barrett
N. A.
.
2016
.
Phosphoinositide 3-kinase δ regulates dectin-2 signaling and the generation of Th2 and Th17 immunity.
J. Immunol.
197
:
278
287
.
107
Lee
W. B.
,
Kang
J. S.
,
Choi
W. Y.
,
Zhang
Q.
,
Kim
C. H.
,
Choi
U. Y.
,
Kim-Ha
J.
,
Kim
Y. J.
.
2016
.
Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution.
Nat. Commun.
7
:
11322
.
108
Ritter
M.
,
Gross
O.
,
Kays
S.
,
Ruland
J.
,
Nimmerjahn
F.
,
Saijo
S.
,
Tschopp
J.
,
Layland
L. E.
,
Prazeres da Costa
C.
.
2010
.
Schistosoma mansoni triggers dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses.
Proc. Natl. Acad. Sci. USA
107
:
20459
20464
.
109
Saïd-Sadier
N.
,
Padilla
E.
,
Langsley
G.
,
Ojcius
D. M.
.
2010
.
Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase.
PLoS One
5
:
e10008
.
110
Kankkunen
P.
,
Teirilä
L.
,
Rintahaka
J.
,
Alenius
H.
,
Wolff
H.
,
Matikainen
S.
.
2010
.
(1,3)-β-glucans activate both dectin-1 and NLRP3 inflammasome in human macrophages.
J. Immunol.
184
:
6335
6342
.
111
Desel
C.
,
Werninghaus
K.
,
Ritter
M.
,
Jozefowski
K.
,
Wenzel
J.
,
Russkamp
N.
,
Schleicher
U.
,
Christensen
D.
,
Wirtz
S.
,
Kirschning
C.
, et al
.
2013
.
The mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling.
PLoS One
8
:
e53531
.
112
Schweneker
K.
,
Gorka
O.
,
Schweneker
M.
,
Poeck
H.
,
Tschopp
J.
,
Peschel
C.
,
Ruland
J.
,
Gross
O.
.
2013
.
The mycobacterial cord factor adjuvant analogue trehalose-6,6′-dibehenate (TDB) activates the Nlrp3 inflammasome.
Immunobiology
218
:
664
673
.
113
Ozinsky
A.
,
Underhill
D. M.
,
Fontenot
J. D.
,
Hajjar
A. M.
,
Smith
K. D.
,
Wilson
C. B.
,
Schroeder
L.
,
Aderem
A.
.
2000
.
The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors.
Proc. Natl. Acad. Sci. USA
97
:
13766
13771
.
114
Jin
M. S.
,
Kim
S. E.
,
Heo
J. Y.
,
Lee
M. E.
,
Kim
H. M.
,
Paik
S.-G.
,
Lee
H.
,
Lee
J.-O.
.
2007
.
Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.
Cell
130
:
1071
1082
.
115
Kang
J. Y.
,
Nan
X.
,
Jin
M. S.
,
Youn
S.-J.
,
Ryu
Y. H.
,
Mah
S.
,
Han
S. H.
,
Lee
H.
,
Paik
S.-G.
,
Lee
J.-O.
.
2009
.
Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer.
Immunity
31
:
873
884
.
116
Bugarcic
A.
,
Hitchens
K.
,
Beckhouse
A. G.
,
Wells
C. A.
,
Ashman
R. B.
,
Blanchard
H.
.
2008
.
Human and mouse macrophage-inducible C-type lectin (mincle) bind Candida albicans.
Glycobiology
18
:
679
685
.
117
Lobato-Pascual
A.
,
Saether
P. C.
,
Fossum
S.
,
Dissen
E.
,
Daws
M. R.
.
2013
.
Mincle, the receptor for mycobacterial cord factor, forms a functional receptor complex with MCL and FcεRI-γ.
Eur. J. Immunol.
43
:
3167
3174
.
118
Miyake
Y.
,
Masatsugu
O. H.
,
Yamasaki
S.
.
2015
.
C-type lectin receptor MCL facilitates Mincle expression and signaling through complex formation.
J. Immunol.
194
:
5366
5374
.
119
Kerscher
B.
,
Wilson
G. J.
,
Reid
D. M.
,
Mori
D.
,
Taylor
J. A.
,
Besra
G. S.
,
Yamasaki
S.
,
Willment
J. A.
,
Brown
G. D.
.
2016
.
Mycobacterial receptor, Clec4d (CLECSF8, MCL), is coregulated with mincle and upregulated on mouse myeloid cells following microbial challenge.
Eur. J. Immunol.
46
:
381
389
.
120
Zhao
X. Q.
,
Zhu
L. L.
,
Chang
Q.
,
Jiang
C.
,
You
Y.
,
Luo
T.
,
Jia
X. M.
,
Lin
X.
.
2014
.
C-type lectin receptor dectin-3 mediates trehalose 6,6′-dimycolate (TDM)-induced Mincle expression through CARD9/Bcl10/MALT1-dependent nuclear factor (NF)-κB activation.
J. Biol. Chem.
289
:
30052
30062
.
121
Yamasaki
S.
2013
.
Signaling while eating: MCL is coupled with mincle.
Eur. J. Immunol.
43
:
3156
3158
.
122
Ostrop
J.
,
Jozefowski
K.
,
Zimmermann
S.
,
Hofmann
K.
,
Strasser
E.
,
Lepenies
B.
,
Lang
R.
.
2015
.
Contribution of MINCLE-SYK signaling to activation of primary human APCs by mycobacterial cord factor and the novel adjuvant TDB.
J. Immunol.
195
:
2417
2428
.
123
Willment
J. A.
,
Lin
H.H.
,
Reid
D. M.
,
Taylor
P. R.
,
Williams
D. L.
,
Wong
S. Y.
,
Gordon
S.
,
Brown
G. D.
.
2003
.
Dectin-1 expression and function are enhanced on alternatively activated and GM-CSF-treated macrophages and are negatively regulated by IL-10, dexamethasone, and lipopolysaccharide.
J. Immunol.
171
:
4569
4573
.
124
Taylor
P. R.
,
Tsoni
S. V.
,
Willment
J. A.
,
Dennehy
K. M.
,
Rosas
M.
,
Findon
H.
,
Haynes
K.
,
Steele
C.
,
Botto
M.
,
Gordon
S.
,
Brown
G. D.
.
2007
.
Dectin-1 is required for β-glucan recognition and control of fungal infection.
Nat. Immunol.
8
:
31
38
.
125
Fairbairn
L.
,
Kapetanovic
R.
,
Beraldi
D.
,
Sester
D. P.
,
Tuggle
C. K.
,
Archibald
A. L.
,
Hume
D. A.
.
2013
.
Comparative analysis of monocyte subsets in the pig.
J. Immunol.
190
:
6389
6396
.
126
Gantner
B. N.
,
Simmons
R. M.
,
Canavera
S. J.
,
Akira
S.
,
Underhill
D. M.
.
2003
.
Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2.
J. Exp. Med.
197
:
1107
1117
.
127
Wittmann
A.
,
Lamprinaki
D.
,
Bowles
K. M.
,
Katzenellenbogen
E.
,
Knirel
Y. A.
,
Whitfield
C.
,
Nishimura
T.
,
Matsumoto
N.
,
Yamamoto
K.
,
Iwakura
Y.
,
Saijo
S.
,
Kawasaki
N.
.
2016
.
Dectin-2 recognises mannosylated O-antigens of human opportunistic pathogens and augments lipopolysaccharide activation of myeloid cells
.
J. Biol. Chem.
291
:
17629
17638
.
128
van Bruggen
R.
,
Drewniak
A.
,
Jansen
M.
,
van Houdt
M.
,
Roos
D.
,
Chapel
H.
,
Verhoeven
A. J.
,
Kuijpers
T. W.
.
2009
.
Complement receptor 3, not dectin-1, is the major receptor on human neutrophils for β-glucan-bearing particles.
Mol. Immunol.
47
:
575
581
.
129
O’Brien
X. M.
,
Heflin
K. E.
,
Lavigne
L. M.
,
Yu
K.
,
Kim
M.
,
Salomon
A. R.
,
Reichner
J. S.
.
2012
.
Lectin site ligation of CR3 induces conformational changes and signaling.
J. Biol. Chem.
287
:
3337
3348
.
130
Bose
N.
,
Wurst
L. R.
,
Chan
A. S.
,
Dudney
C. M.
,
LeRoux
M. L.
,
Danielson
M. E.
,
Will
P. M.
,
Nodland
S. E.
,
Patchen
M. L.
,
Dalle Lucca
J. J.
, et al
.
2014
.
Differential regulation of oxidative burst by distinct β-glucan-binding receptors and signaling pathways in human peripheral blood mononuclear cells.
Glycobiology
24
:
379
391
.
131
Han
C.
,
Jin
J.
,
Xu
S.
,
Liu
H.
,
Li
N.
,
Cao
X.
.
2010
.
Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b.
Nat. Immunol.
11
:
734
742
.
132
Wang
L.
,
Gordon
R. A.
,
Huynh
L.
,
Su
X.
,
Park Min
K. H.
,
Han
J.
,
Arthur
J. S.
,
Kalliolias
G. D.
,
Ivashkiv
L. B.
.
2010
.
Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins.
Immunity
32
:
518
530
.
133
Wirnsberger
G.
,
Zwolanek
F.
,
Asaoka
T.
,
Kozieradzki
I.
,
Tortola
L.
,
Wimmer
R. A.
,
Kavirayani
A.
,
Fresser
F.
,
Baier
G.
,
Langdon
W. Y.
, et al
.
2016
.
Inhibition of CBLB protects from lethal Candida albicans sepsis.
Nat. Med.
22
:
915
923
.
134
Xiao
Y.
,
Tang
J.
,
Guo
H.
,
Zhao
Y.
,
Tang
R.
,
Ouyang
S.
,
Zeng
Q.
,
Rappleye
C. A.
,
Rajaram
M. V.
,
Schlesinger
L. S.
, et al
.
2016
.
Targeting CBLB as a potential therapeutic approach for disseminated candidiasis.
Nat. Med.
22
:
906
914
.
135
Zhu
L.-L.
,
Luo
T.-M.
,
Xu
X.
,
Guo
Y.-H.
,
Zhao
X.-Q.
,
Wang
T.-T.
,
Tang
B.
,
Jiang
Y.-Y.
,
Xu
J.-F.
,
Lin
X.
,
Jia
X.-M.
.
2016
.
E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity.
J. Exp. Med.
213
:
1555
1570
.
136
Brown
G. D.
,
Herre
J.
,
Williams
D. L.
,
Willment
J. A.
,
Marshall
A. S.
,
Gordon
S.
.
2003
.
Dectin-1 mediates the biological effects of β-glucans.
J. Exp. Med.
197
:
1119
1124
.
137
Dennehy
K. M.
,
Ferwerda
G.
,
Faro-Trindade
I.
,
Pyz
E.
,
Willment
J. A.
,
Taylor
P. R.
,
Kerrigan
A.
,
Tsoni
S. V.
,
Gordon
S.
,
Meyer-Wentrup
F.
, et al
.
2008
.
Syk kinase is required for collaborative cytokine production induced through dectin-1 and Toll-like receptors.
Eur. J. Immunol.
38
:
500
506
.
138
Dragicevic
A.
,
Dzopalic
T.
,
Vasilijic
S.
,
Vucevic
D.
,
Tomic
S.
,
Bozic
B.
,
Colic
M.
.
2012
.
Signaling through Toll-like receptor 3 and dectin-1 potentiates the capability of human monocyte-derived dendritic cells to promote T-helper 1 and T-helper 17 immune responses.
Cytotherapy
14
:
598
607
.
139
Dennehy
K. M.
,
Willment
J. A.
,
Williams
D. L.
,
Brown
G. D.
.
2009
.
Reciprocal regulation of IL-23 and IL-12 following co-activation of dectin-1 and TLR signaling pathways.
Eur. J. Immunol.
39
:
1379
1386
.
140
Goodridge
H. S.
,
Shimada
T.
,
Wolf
A. J.
,
Hsu
Y.-M. S.
,
Becker
C. A.
,
Lin
X.
,
Underhill
D. M.
.
2009
.
Differential use of CARD9 by dectin-1 in macrophages and dendritic cells.
J. Immunol.
182
:
1146
1154
.
141
Ferwerda
G.
,
Meyer-Wentrup
F.
,
Kullberg
B.-J.
,
Netea
M. G.
,
Adema
G. J.
.
2008
.
Dectin-1 synergizes with TLR2 and TLR4 for cytokine production in human primary monocytes and macrophages.
Cell. Microbiol.
10
:
2058
2066
.
142
Dillon
S.
,
Agrawal
S.
,
Banerjee
K.
,
Letterio
J.
,
Denning
T. L.
,
Oswald-Richter
K.
,
Kasprowicz
D. J.
,
Kellar
K.
,
Pare
J.
,
van Dyke
T.
, et al
.
2006
.
Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance.
J. Clin. Invest.
116
:
916
928
.
143
Min
L.
,
Isa
S. A.
,
Fam
W. N.
,
Sze
S. K.
,
Beretta
O.
,
Mortellaro
A.
,
Ruedl
C.
.
2012
.
Synergism between curdlan and GM-CSF confers a strong inflammatory signature to dendritic cells.
J. Immunol.
188
:
1789
1798
.
144
Elcombe
S. E.
,
Naqvi
S.
,
Van Den Bosch
M. W.
,
MacKenzie
K. F.
,
Cianfanelli
F.
,
Brown
G. D.
,
Arthur
J. S.
.
2013
.
Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers.
PLoS One
8
:
e60086
.
145
Sousa
Mda. G.
,
Reid
D. M.
,
Schweighoffer
E.
,
Tybulewicz
V.
,
Ruland
J.
,
Langhorne
J.
,
Yamasaki
S.
,
Taylor
P. R.
,
Almeida
S. R.
,
Brown
G. D.
.
2011
.
Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin.
Cell Host Microbe
9
:
436
443
.
146
Patin
E. C.
,
Willcocks
S.
,
Orr
S.
,
Ward
T. H.
,
Lang
R.
,
Schaible
U. E.
.
2016
.
Mincle-mediated anti-inflammatory IL-10 response counter-regulates IL-12 in vitro.
Innate Immun.
22
:
181
185
.
147
Kerscher
B.
,
Dambuza
I. M.
,
Christofi
M.
,
Reid
D. M.
,
Yamasaki
S.
,
Willment
J. A.
,
Brown
G. D.
.
2016
.
Signalling through MyD88 drives surface expression of the mycobacterial receptors MCL (Clecsf8, Clec4d) and Mincle (Clec4e) following microbial stimulation.
Microbes Infect.
18
:
505
509
.
148
Netea
M. G.
,
Quintin
J.
,
van der Meer
J. W.
.
2011
.
Trained immunity: a memory for innate host defense.
Cell Host Microbe
9
:
355
361
.
149
Cheng
S.-C.
,
Quintin
J.
,
Cramer
R. A.
,
Shepardson
K. M.
,
Saeed
S.
,
Kumar
V.
,
Giamarellos-Bourboulis
E. J.
,
Martens
J. H.
,
Rao
N. A.
,
Aghajanirefah
A.
, et al
.
2014
.
mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity.
Science
345
:
1250684
.
150
Saeed
S.
,
Quintin
J.
,
Kerstens
H. H.
,
Rao
N. A.
,
Aghajanirefah
A.
,
Matarese
F.
,
Cheng
S. C.
,
Ratter
J.
,
Berentsen
K.
,
van der Ent
M. A.
, et al
.
2014
.
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.
Science
345
:
1251086
.
151
Trinath
J.
,
Holla
S.
,
Mahadik
K.
,
Prakhar
P.
,
Singh
V.
,
Balaji
K. N.
.
2014
.
The WNT signaling pathway contributes to dectin-1-dependent inhibition of Toll-like receptor-induced inflammatory signature.
Mol. Cell. Biol.
34
:
4301
4314
.
152
Orr
S. J.
,
Burg
A. R.
,
Chan
T.
,
Quigley
L.
,
Jones
G. W.
,
Ford
J. W.
,
Hodge
D.
,
Razzook
C.
,
Sarhan
J.
,
Jones
Y. L.
, et al
.
2013
.
LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.
PLoS Pathog.
9
:
e1003357
.
153
Wüthrich
M.
,
Wang
H.
,
Li
M.
,
Lerksuthirat
T.
,
Hardison
S. E.
,
Brown
G. D.
,
Klein
B.
.
2015
.
Fonsecaea pedrosoi-induced Th17-cell differentiation in mice is fostered by dectin-2 and suppressed by mincle recognition.
Eur. J. Immunol.
45
:
2542
2552
.
154
Seifert
L.
,
Deutsch
M.
,
Alothman
S.
,
Alqunaibit
D.
,
Werba
G.
,
Pansari
M.
,
Pergamo
M.
,
Ochi
A.
,
Torres-Hernandez
A.
,
Levie
E.
, et al
.
2015
.
Dectin-1 regulates hepatic fibrosis and hepatocarcinogenesis by suppressing TLR4 signaling pathways.
Cell Reports
13
:
1909
1921
.
155
Greco
S. H.
,
Mahmood
S. K.
,
Vahle
A. K.
,
Ochi
A.
,
Batel
J.
,
Deutsch
M.
,
Barilla
R.
,
Seifert
L.
,
Pachter
H. L.
,
Daley
D.
, et al
.
2016
.
Mincle suppresses Toll-like receptor 4 activation.
J. Leukoc. Biol.
100
:
185
194
.
156
Seifert
L.
,
Werba
G.
,
Tiwari
S.
,
Giao Ly
N. N.
,
Alothman
S.
,
Alqunaibit
D.
,
Avanzi
A.
,
Barilla
R.
,
Daley
D.
,
Greco
S. H.
, et al
.
2016
.
The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.
Nature
532
:
245
249
.
157
Greco
S. H.
,
Torres-Hernandez
A.
,
Kalabin
A.
,
Whiteman
C.
,
Rokosh
R.
,
Ravirala
S.
,
Ochi
A.
,
Gutierrez
J.
,
Salyana
M. A.
,
Mani
V. R.
, et al
.
2016
.
Mincle signaling promotes Con A hepatitis.
J. Immunol.
197
:
2816
2827
.
158
Steichen
A. L.
,
Binstock
B. J.
,
Mishra
B. B.
,
Sharma
J.
.
2013
.
C-type lectin receptor Clec4d plays a protective role in resolution of gram-negative pneumonia.
J. Leukoc. Biol.
94
:
393
398
.
159
Hole
C. R.
,
Leopold Wager
C. M.
,
Mendiola
A. S.
,
Wozniak
K. L.
,
Campuzano
A.
,
Lin
X.
,
Wormley
F. L.
.
2016
.
Anti-fungal activity of plasmacytoid dendritic cells against Cryptococcus neoformanss in vitro requires expression of dectin-3 (CLEC4D) and reactive oxygen species.
Infect. Immun.
84
:
2493
2504
.
160
Zhou
H.
,
Yu
M.
,
Zhao
J.
,
Martin
B. N.
,
Roychowdhury
S.
,
McMullen
M. R.
,
Wang
E.
,
Fox
P. L.
,
Yamasaki
S.
,
Nagy
L. E.
,
Li
X.
.
2016
.
IRAKM-Mincle axis links cell death to inflammation: pathophysiological implications for chronic alcoholic liver disease.
Hepatology
64
:
1978
1993
.
161
Devi
S.
,
Rajakumara
E.
,
Ahmed
N.
.
2015
.
Induction of mincle by Helicobacter pylori and consequent anti-inflammatory signaling denote a bacterial survival strategy.
Sci. Rep.
5
:
15049
.
162
Sharma
A.
,
Steichen
A. L.
,
Jondle
C. N.
,
Mishra
B. B.
,
Sharma
J.
.
2014
.
Protective role of mincle in bacterial pneumonia by regulation of neutrophil mediated phagocytosis and extracellular trap formation.
J. Infect. Dis.
209
:
1837
1846
.
163
Rabes
A.
,
Zimmermann
S.
,
Reppe
K.
,
Lang
R.
,
Seeberger
P. H.
,
Suttorp
N.
,
Witzenrath
M.
,
Lepenies
B.
,
Opitz
B.
.
2015
.
The C-type lectin receptor mincle binds to Streptococcus pneumoniae but plays a limited role in the anti-pneumococcal innate immune response.
PLoS One
10
:
e0117022
.
164
Shah
S.
,
Nagata
M.
,
Yamasaki
S.
,
Williams
S. J.
.
2016
.
Total synthesis of a cyclopropane-fatty acid α-glucosyl diglyceride from Lactobacillus plantarum and identification of its ability to signal through Mincle.
Chem. Commun. (Camb.)
52
:
10902
10905
.
165
Richardson
M. B.
,
Torigoe
S.
,
Yamasaki
S.
,
Williams
S. J.
.
2015
.
Mycobacterium tuberculosis β-gentiobiosyl diacylglycerides signal through the pattern recognition receptor mincle: total synthesis and structure activity relationships.
Chem. Commun. (Camb.)
51
:
15027
15030
.
166
Vijayan
D.
,
Radford
K. J.
,
Beckhouse
A. G.
,
Ashman
R. B.
,
Wells
C. A.
.
2012
.
Mincle polarizes human monocyte and neutrophil responses to Candida albicans.
Immunol. Cell Biol.
90
:
889
895
.
167
Ishikawa
T.
,
Itoh
F.
,
Yoshida
S.
,
Saijo
S.
,
Matsuzawa
T.
,
Gonoi
T.
,
Saito
T.
,
Okawa
Y.
,
Shibata
N.
,
Miyamoto
T.
,
Yamasaki
S.
.
2013
.
Identification of distinct ligands for the C-type lectin receptors Mincle and dectin-2 in the pathogenic fungus Malassezia.
Cell Host Microbe
13
:
477
488
.
168
Khan
A. A.
,
Chee
S. H.
,
McLaughlin
R. J.
,
Harper
J. L.
,
Kamena
F.
,
Timmer
M. S.
,
Stocker
B. L.
.
2011
.
Long-chain lipids are required for the innate immune recognition of trehalose diesters by macrophages.
ChemBioChem
12
:
2572
2576
.
169
Stocker
B. L.
,
Timmer
M. S.
.
2014
.
Trehalose diesters, lipoteichoic acids and α-GalCer: using chemistry to understand immunology.
Carbohydr. Res.
389
:
3
11
.
170
Wells
C. A.
,
Salvage-Jones
J. A.
,
Li
X.
,
Hitchens
K.
,
Butcher
S.
,
Murray
R. Z.
,
Beckhouse
A. G.
,
Lo
Y.L.
,
Manzanero
S.
,
Cobbold
C.
, et al
.
2008
.
The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans.
J. Immunol.
180
:
7404
7413
.
171
Yamasaki
S.
,
Matsumoto
M.
,
Takeuchi
O.
,
Matsuzawa
T.
,
Ishikawa
E.
,
Sakuma
M.
,
Tateno
H.
,
Uno
J.
,
Hirabayashi
J.
,
Mikami
Y.
, et al
.
2009
.
C-type lectin mincle is an activating receptor for pathogenic fungus, Malassezia.
Proc. Natl. Acad. Sci. USA
106
:
1897
1902
.
172
Aragane
Y.
,
Maeda
A.
,
Schwarz
A.
,
Tezuka
T.
,
Ariizumi
K.
,
Schwarz
T.
.
2003
.
Involvement of dectin-2 in ultraviolet radiation-induced tolerance.
J. Immunol.
171
:
3801
3807
.
173
McGreal
E. P.
,
Rosas
M.
,
Brown
G. D.
,
Zamze
S.
,
Wong
S. Y.
,
Gordon
S.
,
Martinez-Pomares
L.
,
Taylor
P. R.
.
2006
.
The carbohydrate-recognition domain of dectin-2 is a C-type lectin with specificity for high mannose.
Glycobiology
16
:
422
430
.
174
Akahori
Y.
,
Miyasaka
T.
,
Toyama
M.
,
Matsumoto
I.
,
Miyahara
A.
,
Zong
T.
,
Ishii
K.
,
Kinjo
Y.
,
Miyazaki
Y.
,
Saijo
S.
, et al
.
2016
.
Dectin-2-dependent host defense in mice infected with serotype 3 Streptococcus pneumoniae.
BMC Immunol.
17
:
1
.
175
Yonekawa
A.
,
Saijo
S.
,
Hoshino
Y.
,
Miyake
Y.
,
Ishikawa
E.
,
Suzukawa
M.
,
Inoue
H.
,
Tanaka
M.
,
Yoneyama
M.
,
Oh-Hora
M.
, et al
.
2014
.
Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria.
Immunity
41
:
402
413
.
176
Loures
F. V.
,
Röhm
M.
,
Lee
C. K.
,
Santos
E.
,
Wang
J. P.
,
Specht
C. A.
,
Calich
V. L.
,
Urban
C. F.
,
Levitz
S. M.
.
2015
.
Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps.
PLoS Pathog.
11
:
e1004643
.
177
Wang
H.
,
LeBert
V.
,
Hung
C. Y.
,
Galles
K.
,
Saijo
S.
,
Lin
X.
,
Cole
G. T.
,
Klein
B. S.
,
Wüthrich
M.
.
2014
.
C-type lectin receptors differentially induce th17 cells and vaccine immunity to the endemic mycosis of North America.
J. Immunol.
192
:
1107
1119
.
178
Ifrim
D. C.
,
Bain
J. M.
,
Reid
D. M.
,
Oosting
M.
,
Verschueren
I.
,
Gow
N. A.
,
van Krieken
J. H.
,
Brown
G. D.
,
Kullberg
B.J.
,
Joosten
L. A.
, et al
.
2014
.
Role of dectin-2 for host defense against systemic infection with Candida glabrata.
Infect. Immun.
82
:
1064
1073
.
179
Nakamura
Y.
,
Sato
K.
,
Yamamoto
H.
,
Matsumura
K.
,
Matsumoto
I.
,
Nomura
T.
,
Miyasaka
T.
,
Ishii
K.
,
Kanno
E.
,
Tachi
M.
, et al
.
2015
.
Dectin-2 deficiency promotes Th2 response and mucin production in the lungs after pulmonary infection with Cryptococcus neoformans.
Infect. Immun.
83
:
671
681
.
180
Yoshikawa
F. S.
,
Yabe
R.
,
Iwakura
Y.
,
de Almeida
S. R.
,
Saijo
S.
.
2016
.
Dectin-1 and dectin-2 promote control of the fungal pathogen Trichophyton rubrum independently of IL-17 and adaptive immunity in experimental deep dermatophytosis.
Innate Immun.
22
:
316
324
.
181
Barrett
N. A.
,
Maekawa
A.
,
Rahman
O. M.
,
Austen
K. F.
,
Kanaoka
Y.
.
2009
.
Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells.
J. Immunol.
182
:
1119
1128
.
182
Ariizumi
K.
,
Shen
G.-L.
,
Shikano
S.
,
Xu
S.
,
Ritter
R.
 III
,
Kumamoto
T.
,
Edelbaum
D.
,
Morita
A.
,
Bergstresser
P. R.
,
Takashima
A.
.
2000
.
Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning.
J. Biol. Chem.
275
:
20157
20167
.
183
Rao
R.
,
Graffeo
C. S.
,
Gulati
R.
,
Jamal
M.
,
Narayan
S.
,
Zambirinis
C. P.
,
Barilla
R.
,
Deutsch
M.
,
Greco
S. H.
,
Ochi
A.
, et al
.
2014
.
Interleukin 17-producing γδT cells promote hepatic regeneration in mice.
Gastroenterology
147
:
473
484.e2
.
184
Thiagarajan
P. S.
,
Yakubenko
V. P.
,
Elsori
D. H.
,
Yadav
S. P.
,
Willard
B.
,
Tan
C. D.
,
Rodriguez
E. R.
,
Febbraio
M.
,
Cathcart
M. K.
.
2013
.
Vimentin is an endogenous ligand for the pattern recognition receptor dectin-1.
Cardiovasc. Res.
99
:
494
504
.
185
Ahrén
I. L.
,
Eriksson
E.
,
Egesten
A.
,
Riesbeck
K.
.
2003
.
Nontypeable Haemophilus influenzae activates human eosinophils through beta-glucan receptors.
Am. J. Respir. Cell Mol. Biol.
29
:
598
605
.
186
Heyl
K. A.
,
Klassert
T. E.
,
Heinrich
A.
,
Müller
M. M.
,
Klaile
E.
,
Dienemann
H.
,
Grünewald
C.
,
Bals
R.
,
Singer
B. B.
,
Slevogt
H.
.
2014
.
Dectin-1 is expressed in human lung and mediates the proinflammatory immune response to nontypeable Haemophilus influenzae.
MBio
5
:
e01492–e14
.
187
Rothfuchs
A. G.
,
Bafica
A.
,
Feng
C. G.
,
Egen
J. G.
,
Williams
D. L.
,
Brown
G. D.
,
Sher
A.
.
2007
.
Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells.
J. Immunol.
179
:
3463
3471
.
188
Shin
D.-M.
,
Yang
C.-S.
,
Yuk
J.-M.
,
Lee
J.-Y.
,
Kim
K. H.
,
Shin
S. J.
,
Takahara
K.
,
Lee
S. J.
,
Jo
E.-K.
.
2008
.
Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1.
Cell. Microbiol.
10
:
1608
1621
.
189
Gersuk
G. M.
,
Underhill
D. M.
,
Zhu
L.
,
Marr
K. A.
.
2006
.
Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states.
J. Immunol.
176
:
3717
3724
.
190
Hohl
T. M.
,
Van Epps
H. L.
,
Rivera
A.
,
Morgan
L. A.
,
Chen
P. L.
,
Feldmesser
M.
,
Pamer
E. G.
.
2005
.
Aspergillus fumigatus triggers inflammatory responses by stage-specific β-glucan display.
PLoS Pathog.
1
:
e30
.
191
Steele
C.
,
Rapaka
R. R.
,
Metz
A.
,
Pop
S. M.
,
Williams
D. L.
,
Gordon
S.
,
Kolls
J. K.
,
Brown
G. D.
.
2005
.
The β-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.
PLoS Pathog.
1
:
e42
.
192
Werner
J. L.
,
Metz
A. E.
,
Horn
D.
,
Schoeb
T. R.
,
Hewitt
M. M.
,
Schwiebert
L. M.
,
Faro-Trindade
I.
,
Brown
G. D.
,
Steele
C.
.
2009
.
Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus.
J. Immunol.
182
:
4938
4946
.
193
Gantner
B. N.
,
Simmons
R. M.
,
Underhill
D. M.
.
2005
.
Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments.
EMBO J.
24
:
1277
1286
.
194
Gow
N. A.
,
Netea
M. G.
,
Munro
C. A.
,
Ferwerda
G.
,
Bates
S.
,
Mora-Montes
H. M.
,
Walker
L.
,
Jansen
T.
,
Jacobs
L.
,
Tsoni
V.
, et al
.
2007
.
Immune recognition of Candida albicans β-glucan by dectin-1.
J. Infect. Dis.
196
:
1565
1571
.
195
Viriyakosol
S.
,
Jimenez
Mdel. P.
,
Saijo
S.
,
Fierer
J.
.
2014
.
Neither dectin-2 nor the mannose receptor is required for resistance to Coccidioides immitis in mice.
Infect. Immun.
82
:
1147
1156
.
196
Rappleye
C. A.
,
Eissenberg
L. G.
,
Goldman
W. E.
.
2007
.
Histoplasma capsulatum α-(1,3)-glucan blocks innate immune recognition by the β-glucan receptor.
Proc. Natl. Acad. Sci. USA
104
:
1366
1370
.
197
Nakamura
K.
,
Miyazato
A.
,
Koguchi
Y.
,
Adachi
Y.
,
Ohno
N.
,
Saijo
S.
,
Iwakura
Y.
,
Takeda
K.
,
Akira
S.
,
Fujita
J.
, et al
.
2008
.
Toll-like receptor 2 (TLR2) and dectin-1 contribute to the production of IL-12p40 by bone marrow-derived dendritic cells infected with Penicillium marneffei.
Microbes Infect.
10
:
1223
1227
.
198
Steele
C.
,
Marrero
L.
,
Swain
S.
,
Harmsen
A. G.
,
Zheng
M.
,
Brown
G. D.
,
Gordon
S.
,
Shellito
J. E.
,
Kolls
J. K.
.
2003
.
Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-1 β-glucan receptor.
J. Exp. Med.
198
:
1677
1688
.
199
Huang
X. Q.
,
Yi
J. L.
,
Yin
S. C.
,
Chen
R. Z.
,
Li
M. R.
,
Gong
Z. J.
,
Lai
W.
,
Chen
J.
.
2013
.
Exposure to heat-inactivated Trichophyton rubrum resulting in a limited immune response of human keratinocytes.
Chin. Med. J. (Engl.)
126
:
215
219
.
200
Higashino-Kameda
M.
,
Yabe-Wada
T.
,
Matsuba
S.
,
Takeda
K.
,
Anzawa
K.
,
Mochizuki
T.
,
Makimura
K.
,
Saijo
S.
,
Iwakura
Y.
,
Toga
H.
,
Nakamura
A.
.
2016
.
A critical role of Dectin-1 in hypersensitivity pneumonitis.
Inflamm. Res.
65
:
235
244
.
201
Brown
G. D.
,
Taylor
P. R.
,
Reid
D. M.
,
Willment
J. A.
,
Williams
D. L.
,
Martinez-Pomares
L.
,
Wong
S. Y. C.
,
Gordon
S.
.
2002
.
Dectin-1 is a major β-glucan receptor on macrophages.
J. Exp. Med.
196
:
407
412
.
202
Palma
A. S.
,
Feizi
T.
,
Zhang
Y.
,
Stoll
M. S.
,
Lawson
A. M.
,
Díaz-Rodríguez
E.
,
Campanero-Rhodes
M. A.
,
Costa
J.
,
Gordon
S.
,
Brown
G. D.
,
Chai
W.
.
2006
.
Ligands for the β-glucan receptor, dectin-1, assigned using “designer” microarrays of oligosaccharide probes (neoglycolipids) generated from glucan polysaccharides.
J. Biol. Chem.
281
:
5771
5779
.
203
Ikeda
Y.
,
Adachi
Y.
,
Ishii
T.
,
Miura
N.
,
Tamura
H.
,
Ohno
N.
.
2008
.
Dissociation of Toll-like receptor 2-mediated innate immune response to Zymosan by organic solvent-treatment without loss of dectin-1 reactivity.
Biol. Pharm. Bull.
31
:
13
18
.
204
Jiang
S.
,
Niu
S.
,
Yao
W.
,
Li
Z.-J.
,
Li
Q.
.
2016
.
Binding activities of non-β-glucan glycoclusters to dectin-1 and exploration of their binding site.
Carbohydr. Res.
429
:
148
154
.

The authors have no financial conflicts of interest.