Galectin-1: A Jack-of-All-Trades in the Resolution of Acute and Chronic Inflammation Free

Resolution of immune responses involves the interplay between anti-inflammatory and proresolving mediators that are rapidly released at times of cellular stress and tissue injury to counterbalance exuberant inflammation, mitigate collateral tissue damage, and orchestrate immune cell homeostasis (1). These include immunosuppressive cytokines (IL-10, TGF-β₁, IL-35), anti-inflammatory neuropeptides (vasoactive intestinal peptide, neuropeptide Y), bioactive lipid molecules (lipoxins, resolvins, protectins), steroid hormones (glucocorticoids), and resolution-associated molecular patterns (RAMPs), including glucose-regulated protein 78, heat shock protein 10, heat shock protein 27, and αβ-crystallin, which together counteract the proinflammatory effects triggered by danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (2, 3).

Galectins, a family of soluble β-galactoside–binding proteins widely expressed at sites of inflammation, infection, and tumor growth, have emerged as a new class of DAMPs or RAMPs that serve to amplify or resolve inflammatory responses (4, 5). Based on their architecture, galectins have been grouped into three subfamilies: “proto-type” galectins, consisting of a single polypeptide chain with one carbohydrate recognition domain (CRD) that can dimerize (galectin-1 [Gal-1], -2, -5, -7, -10, -11, -13, -14, and 15); “tandem repeat-type” galectins composed of a single polypeptide chain exhibiting two CRDs connected by a linker peptide (Gal-4, -6, -8, -9, and -12); and the “chimera-type” Gal-3, which consists of one C-terminal CRD domain linked to an N-terminal domain (6). Once synthesized, galectins may remain inside the cell and control intracellular processes, or they may be released to the extracellular space through a nonconventional pathway that remains unknown (7–10). Whereas one-CRD galectins can dimerize via the back sides of their CRDs, chimera-type Gal-3 can pentamerize via its nonlectin N-terminal domain, and tandem-repeat galectins can oligomerize (11). The formation of multivalent galectin–glycan complexes contributes to the assembly and organization of cell surface receptors, controlling their segregation, internalization, and signaling (6). In fact, galectins can interact with a wide range of glycosylated receptors and trigger distinct signaling programs, including immune cell activation, differentiation, trafficking, and survival (6). Although some members of the galectin family act primarily as proinflammatory mediators, others display broad anti-inflammatory activities; yet, in most circumstances, stimulatory or inhibitory effects vary according to different tissue contexts, intracellular or extracellular localization of these proteins, pathologic conditions, and spatiotemporal expression of other regulatory programs (6, 11). Illustrating this concept, Gal-3 and Gal-9 have been proposed to act as alarmins or DAMPs that orchestrate inflammatory responses during sepsis, parasite infection, and neuroinflammation (5, 12–14), yet these lectins may exhibit immune-inhibitory activities in tumor microenvironments (15, 16).

Gal-1, the first galectin identified, acts typically as a proresolving mediator by repressing a number of innate and adaptive immune programs (4). From a structural standpoint, Gal-1 is composed of two subunits of 14.5 kDa (135 aa) present in a dynamic dimerization equilibrium (4). Because of an unusual number of six cysteine residues, this lectin is highly sensitive to oxidative inactivation, which limits its biological activity (17). Although typically conceived as independent processes, studies suggested that these mechanisms could be interconnected as dimerization favors ligand binding, which protects Gal-1 from oxidative inactivation (18).

Gal-1 recognizes multiple galactose-β1-4–N-acetyl-glucosamine (N-acetyl-lactosamine [LacNAc]) units present on the branches of N- or O-linked glycans on diverse cell surface receptors, including CD45, CD43, CD69, pre-BCR, and vascular endothelial growth factor R2 (11, 19–21). Different glycosyltransferases act in concert to create Gal-1–specific ligands, including N-acetylglucosaminyltransferase 5 (MGAT5), an enzyme that generates β1,6-N-acetylglucosamine–branched complex N-glycans and the core-2 β1-6–N-acetylglucosaminyltransferase 1 (C2GNT1), an enzyme that catalyzes branching of core-2 O-glycans. Conversely, Gal-1 binding is thwarted when LacNAc is modified by α2,6-linked sialic acid incorporated by the α2,6 sialyltransferase 1 (ST6GAL1) (6). Thus, sensitivity to Gal-1 is influenced by intrinsic and extrinsic factors, including dimerization equilibrium, redox status, and the regulated activity of glycosyltransferases responsible for creating or hindering specific glycan structures on target cells (6).

Within the immune system, Gal-1 is synthesized and secreted by a wide range of cells, including activated T and B cells (22, 23), macrophages (24), Foxp3⁺ regulatory T cells (Tregs) (25, 26), tolerogenic dendritic cells (DCs) (27, 28), γδ T cells (29), microglia (30), and myeloid-derived suppressor cells (29). Remarkably, Gal-1 expression is prominent in immune-privileged sites, such as placenta (31, 32), testis (33, 34), and the eye (35), and is significantly up- or downmodulated in inflammatory conditions, including microbial infection (36–38), autoimmunity (27, 39), allergy (40, 41), cancer (19, 29, 42–44), reproductive disorders (31, 32, 45, 46), neurodegenerative diseases (30), and myocardial infarction (47). Interestingly, in experimental models, Gal-1 expression peaks during the recovery phase of autoimmune disease (27, 30), indicating a major role for this lectin during resolution of inflammation. In this article, we focus on the proresolving roles of Gal-1 during acute and chronic inflammatory responses (Fig. 1) and discuss its therapeutic potential in a broad range of physiologic and pathologic conditions.

Three major steps, namely initiation, amplification, and resolution, are involved in acute inflammation (48). Unresolved inflammation may lead to several diseases, such as atherosclerosis, asthma, fibrosis, and metabolic diseases (49). A large body of evidence suggests that Gal-1 mediates anti-inflammatory actions, as well as contributes to actively resolve acute inflammation. Exogenous Gal-1 markedly inhibited acute inflammation induced by administration of phospholipase A2 or carrageenan and attenuated neutrophil infiltration (50–53). However, a low degree of inflammation and leukocyte infiltration was observed in Gal-1–deficient (Lgals1^−/−) mice in a second phase (48–96 h), but not in the first phase (24 h), of edema (53), suggesting distinct roles for endogenous versus exogenous Gal-1 during different stages of the inflammatory response. Mechanistically, exogenous Gal-1 inhibits activation, chemotaxis, and extravasation of neutrophils induced by inflammatory stimuli (52, 53). Moreover, it also promotes cell surface phosphatidylserine exposure, favoring phagocytic removal of viable neutrophils (54). In contrast, this lectin stimulates activation and migration of resting neutrophils (55). Thus, the cellular activation status, which leads to different glycosylation or signaling profiles, might dictate Gal-1 function.

With regard to macrophages, cooperative partners of neutrophils in innate immunity, numerous studies demonstrate that Gal-1 promotes the acquisition of an anti-inflammatory and proresolving profile. By controlling l-arginine metabolism, either by reducing the production of NO or favoring the arginase pathway, Gal-1 promotes differentiation of macrophages into an M2 profile (56). In Trypanosoma cruzi–infected macrophages, Gal-1 inhibited IL-12 and NO production, favoring parasite replication (57). Moreover, through inhibition of MHC class II and FcγR expression (58) and stimulation of 12/15-lipoxygenase expression (59), this lectin favors macrophage conversion into a proresolving phenotype. In addition, Gal-1 stimulated monocyte chemotaxis (60), suggesting that this lectin endows macrophages with a combined proresolving and promigratory phenotype. Likewise, this lectin may impart a distinctive immunoregulatory program in DCs that is characterized by migratory and tolerogenic profiles. Exogenous and endogenous Gal-1 contribute to differentiation of tolerogenic DCs through mechanisms involving IL-27 and IL-10 (27). Accordingly, DCs lacking Gal-1 were consistently more immunogenic than wild-type (WT) DCs, favored polarization toward Th1 and Th17 profiles, and counteracted Treg responses (27, 37). In contrast, Gal-1 promoted DC migration and maturation (61, 62) and inhibited tissue emigration of immunogenic, but not tolerogenic, DCs through mechanisms involving differential core 2 O-glycosylation of CD43 (63). This selective effect provides an additional mechanism for the unique anti-inflammatory function of this lectin involving both tolerogenic and promigratory profiles.

Mounting evidence highlights a major role for Gal-1–glycan interactions in shaping the profile of individual T cell subsets controlling their activation, differentiation, survival, and cytokine production (64). Functional assays identified Gal-1 as a novel CD69-binding partner that controls differentiation of Th17 cells (20). Moreover, Gal-1 has been shown to control T cell survival by interacting with different components of the cell death machinery. Through binding to N- and O-glycans present in CD45, CD43, and CD7 (65), or by sensitizing T cells to the Fas-mediated pathway (66), exogenous Gal-1 has been shown to engage cell death programs. Moreover, recent studies showed that intracellular Gal-1 sensitizes T cells to apoptosis induced by extracellular Gal-1, an effect that was substantiated in cells from systemic lupus erythematosus patients, which express lower Gal-1 levels and are less sensitive to exogenous Gal-1 than T cells from healthy subjects (67). However, other studies showed that recombinant Gal-1 does not promote T cell death in the absence of DTT, a reducing agent used to avoid oxidation of this lectin (68). Notwithstanding, experiments aimed at exploring the relevance of endogenous Gal-1 in vivo revealed changes in T cell viability when this lectin was knocked down in tumor cells (42, 69) or when Lgals1^−/− mice were challenged with inflammatory stimuli (70), suggesting direct or indirect roles for Gal-1 in controlling T cell fate. Using in vitro and in vivo approaches, we found that Gal-1 selectively controls the fate of fully activated Th1- and Th17-polarized cells, because these cells express the repertoire of glycans that are critical for Gal-1 binding, whereas Th2 cells are resistant to this lectin as a result of increased α2,6-sialylation of cell surface glycoproteins (70). This mechanism may account for the enhanced frequency of Th1 and Th17 cells in Ag-challenged Lgals1^−/− mice (70) and may explain Th2-skewed responses induced by Gal-1 in models of autoimmunity and cancer (71). Additionally, Gal-1 may impair T cell function by antagonizing TCR signals (72) and favoring IL-10 secretion (73–76), suggesting multiple pathways used by this lectin to control T cell responses.

In addition to its inhibitory roles in effector T cells, Gal-1 may shape the function of Tregs by supporting their differentiation, expansion, and immunosuppressive potential. In models of pregnancy, parasite infection, autoimmunity, and breast cancer, Gal-1 triggered the expansion and/or recruitment of Tregs (26, 31, 37, 76). Moreover, Foxp3⁺ Tregs (25) and regulatory γδ T cells (29) express high amounts of Gal-1, which contribute to the immunosuppressive function of these cells. Although the precise role of Gal-1 in Treg-induced immunosuppression is still poorly understood, Wang et al. (77) reported a possible mechanism by which Tregs inhibit effector T cells through a Gal-1–driven pathway involving the GM1 ganglioside and the TRPC5 channel. Future studies should be aimed at elucidating the biochemical nature and functional relevance of these interactions in vivo.

With regard to the B cell compartment, Gal-1 was identified as an essential component of the synapse established between stromal bone marrow cells and pre-B cells (78). Ligand-induced pre-BCR activation relied upon interactions among the pre-BCR, Gal-1, and α₄β₁, α₅β₁, and α₄β₇ integrins, leading to pre-BCR clustering and signaling, with the consequent generation of pre-BII/stromal cell niches (79). Notably, the λ5 unique region of the pre-BCR represents an unusual example of a nonglycosylated extracellular protein partner of Gal-1, which docks onto a Gal-1 hydrophobic surface adjacent to its CRD and reduces Gal-1 affinity for LacNAc epitopes (21, 80). Within the mature B cell compartment, Gal-1 amplifies B cell activation by augmenting the strength of BCR signaling (81, 82). In the presence of Gal-1, suboptimal concentrations of anti-IgM triggered full BCR signals in leukemic B cells (81, 82), suggesting that Gal-1–glycan interactions act by decreasing the threshold for B cell activation. Moreover, Gal-1 controls transition of activated B cells toward memory B cell or plasma cell phenotypes (83, 84). Thus, Gal-1 exerts broad influence during the lifespan of immature and mature B cells by modulating immune synapses, signaling, and differentiation.

Studies in different rodent models and human samples revealed critical roles for Gal-1 in the resolution of autoimmune inflammation (64).

By controlling the fate and signaling of T cells, DCs, and CNS immune populations, including microglia, astrocytes, and oligodendrocytes, Gal-1 influences the development, severity, and resolution of experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (85). First reported in Lewis rats (86), Gal-1 reduced clinical signs of EAE through diverse mechanisms (85). Endogenous Gal-1 was selectively upregulated by tolerogenic stimuli, and its expression increased during the peak and resolution phases of EAE (27, 30). Interestingly, Lgals1^−/− mice develop greater Th1 and Th17 responses, enhanced susceptibility to autoimmune neuroinflammation, and greater disease severity than their WT counterparts (70). At the mechanistic level, Gal-1 contributed to the resolution of EAE by selectively deleting Th1 and Th17 cells (70) or by inducing differentiation of tolerogenic DCs, which favor induction of IL-10–producing Tr1 cells through IL-27– and STAT3-dependent mechanisms (27). This immunoregulatory circuit also provided an explanatory mechanism for the underlying i.v. tolerance induced by MOG 35–55 administration (87).

Finally, in addition to its role within T cell and DC compartments, Gal-1 controls microglia polarization and function (30, 88, 89). We found that, in response to immunosuppressive stimuli, astrocytes may limit the activation of classically activated M1 microglia by secreting Gal-1, which hierarchically suppresses downstream proinflammatory mediators, such as inducible NO synthase, TNF, and CCL2, and tempers inflammation-induced neurodegeneration (30). Mice devoid of Gal-1 showed increased microglia activation, astrogliosis, demyelination, and axonal regeneration (30, 88).

Encouraged by its ability to impair T cell function and suppress proinflammatory cytokines (90, 91), the effects of Gal-1 were assessed in a collagen-induced arthritis model by gene and protein therapy strategies (92). Marked amelioration of the disease, enhanced susceptibility to Ag-induced T cell apoptosis, cytokine shift toward a Th2 response, and overall reduction of anti-collagen type II Ab were typical hallmarks of Gal-1–treated mice (92). Accordingly, Gal-1 expression decreased in synovial tissue from patients with juvenile idiopathic arthritis (93) and in joints of arthritic rats (94). These effects contrast with the broad proinflammatory and profibrotic activities of Gal-3 (94, 95), confirming different actions of individual members of the galectin family during the arthritogenic process. Moreover, lack of endogenous Gal-1 led to enhanced disease severity and a pronounced proinflammatory phenotype in Lgals1^−/− arthritic mice (96).

Studies in different models revealed a critical role for Gal-1 in the control of ocular inflammation. Systemic administration of recombinant Gal-1 early or late during the course of experimental autoimmune uveitis decreased leukocyte infiltration, as well as promoted a shift toward Th2 and Treg cytokine profiles, counteracting pathogenic Th1 cells and ameliorating ocular pathology (76). More recently, in a model of endotoxin-induced uveitis, Gal-1 treatment ameliorated clinical manifestations of the disease by decreasing leukocyte infiltration and release of proinflammatory cytokines (97). Likewise, Gal-1 suppressed Pseudomonas aeruginosa–induced corneal inflammation by reducing leukocyte infiltration, inhibiting proinflammatory responses, and favoring Th2- and IL-10–mediated anti-inflammatory programs (36). Interestingly, in a model of ocular immunopathology induced by HSV-1, Gal-1 reduced the severity of keratitis lesions and the extent of corneal vascularization (98).

Endogenous Gal-1 is abundantly expressed in different eye compartments, including cornea and retina (35, 99), and it mediates inhibition of T cell activation induced by retinal pigment epithelial cells (100), suggesting that it may prevent exuberant ocular inflammation. In this regard, increased frequency of neutralizing anti–Gal-1 Ab has been documented in sera from patients with autoimmune uveitis compared with healthy subjects (101). These findings, together with the potent immunosuppressive activity of this lectin, suggest a major role for the Gal-1–glycan axis in sustaining immune privilege and restraining ocular inflammation.

Expression of Gal-1 is prominent in different cell types within the testis, including Sertoli cells and germ cells (33, 34, 102). In vitro, Gal-1 synthesized by Sertoli cells favored the differentiation of tolerogenic DCs (102), suggesting its potential role in creating an immunosuppressive testicular microenvironment. In contrast to other experimental models, Lgals1^−/− mice showed reduced incidence and severity of experimental autoimmune orchitis compared with WT mice (34). However, administration of recombinant Gal-1 attenuated disease severity (34), suggesting different roles for endogenous versus exogenous Gal-1 in the regulation of testicular inflammation. Moreover, although a substantial increase in Gal-1 was reported during the peak of inflammation in other models (85), testis immunopathology was not associated with upregulation of this lectin (34). These results suggest context-dependent regulation of Gal-1 expression and function in the control of autoimmune inflammation.

Given the ability of Gal-1 to target activated T cells, this lectin became a promising tool to treat type 1 diabetes (T1D) (103). In NOD mice, therapy with soluble Gal-1 prevented the onset of the disease (103). The preventive effect of Gal-1 on T1D was significantly associated with a reduction in Th1 immunity and increased frequency of IL-10– and IL-4–secreting CD4 T cells in response to pancreatic β cell Ag. In accordance with previous studies (92), this lectin induced apoptosis of pathogenic T cells (103).

In T1D, pancreatic β cell destruction results from activation of Ag-specific effector T cells evading the protective roles of Tregs (104). A primary defect in effector T cells that confers resistance to Treg suppression was suggested in NOD mice and subjects with T1D (104, 105). Notably, lack of GM1 expression by effector T cells preventing Gal-1 binding has been proposed as a potential mechanism of resistance to Treg-induced immunosuppression (77, 106). However, because Gal-1 binds to a variety of glycoconjugates (11), further studies are warranted to elucidate whether other galectin–receptor interactions might take place under these circumstances. Finally, in contrast to healthy pregnant women, patients with gestational diabetes mellitus did not show any significant changes in Gal-1 levels during gestation (46). Of note, an immune-endocrine circuit regulated during the resolution of T1D and gestational diabetes mellitus may govern the broad immunosuppressive activities of Gal-1, leading to Th2 cytokine polarization (70, 107) and Treg expansion (26, 31, 103).

Inflammatory bowel diseases (IBDs) are chronic relapsing inflammatory disorders that affect the gastrointestinal tract. Crohn’s disease and ulcerative colitis represent the two main forms of IBD, which differ in their anatomical, histological, and immunological features. Although Crohn’s disease patients exhibit pronounced Th1 and Th17 responses, T cells from ulcerative colitis patients typically display a Th2 bias (108). Nevertheless, both pathologic conditions involve an aberrant activation of mucosal T cells against commensal microbiota, leading to inflammation and epithelial cell deregulation (109).

Several members of the galectin family, including Gal-1, -2, -3, and -4, play important roles in IBD (110–113). Treatment with Gal-1 resulted in improvement of clinical, histopathological, and immunological manifestations of intestinal inflammation in the 2,4,6-trinitrobenzenesulfonic acid–induced colitis model (39). In addition to normalization of mucosal architecture, administration of exogenous Gal-1 induced apoptosis of activated CD4⁺ T cells in lamina propria and spleen and diminished the levels of proinflammatory cytokines in plasma and mucosal tissue (39). Interestingly, in human samples, Gal-1, -3, -4, and -9 were found to be homogeneously expressed throughout the colon, and their expression was higher in the colon than in the small intestine (114). Notably, unlike Gal-3, -4, and -9, Gal-1 expression was upregulated in inflamed versus noninflamed areas of IBD patients. Using a multivariate-linear discriminant analysis, a specific galectin signature could be identified that distinguished inflamed IBD from control tissue or from other intestinal inflammatory conditions (114). Inflammatory stimuli controlled Gal-1 binding to epithelial cells, influencing epithelial cell survival and production of tolerogenic cytokines (IL-10, IL-25, and TGF-β₁) (115, 116). Thus, either through elimination of Ag-experienced T cells or through modulation of inflammatory cytokines, Gal-1 promotes the resolution of gut inflammation, acting as a RAMP in mucosal homeostasis. These results integrate Gal-1 into the tolerogenic portfolio that coordinates the interplay between intestinal epithelial cells and the highly specialized gut immune system.

Allergic reactions occur clinically as anaphylaxis, urticaria, angioedema, rhinitis, atopic dermatitis, and asthma. A major breakthrough in understanding asthma pathogenesis was the recent characterization of different endotypes on the basis of distinct pathological mechanisms, such as Th2-high asthma and Th2-low asthma (117). Recent observations suggest that Gal-1 plays an important role in the control of airway infiltration by eosinophils. In a model of allergic asthma, allergen-challenged Lgals1^−/−mice showed an increased airway infiltration by eosinophils and T lymphocytes, as well as higher numbers of peripheral blood eosinophils, compared with WT mice (40). Consistent with these observations, Lgals1^−/− mice showed more severe airway hyperresponsiveness associated with higher levels of TNF in the lung. Through inhibition of cell migration or induction of eosinophil apoptosis, Gal-1 reduced eosinophil recruitment to the airways (40). The ability of Gal-1 to inhibit cell migration may not be restricted to eosinophils, because this lectin also inhibits lymphocyte trafficking in vitro and in vivo (118). Supporting the role for Gal-1 in the pathogenesis of asthma, macrophages from sputum samples of asthma patients expressed lower Gal-1 levels than those isolated from healthy donors (119). Interestingly, corticosteroids, the first-line and most effective treatment for asthma, induced a pronounced increase in Gal-1 expression in human nasal polyps, suggesting that glucocorticoids’ action in asthmatic patients could be partially mediated through an increased synthesis of Gal-1 in the airways (120, 121). In a murine model of oral allergy syndrome, administration of Gal-1 suppressed allergic reaction induced by food allergens by inhibiting IL-4 production, recruitment of mast cells and eosinophils, and synthesis of histamine (41). More recently, Gal-1 has been shown to synergize with allergen-specific immunotherapy, providing long-term benefits in animal models by targeting mast cells and facilitating Treg development (122). Overall, these reports suggest that Gal-1 influences the resolution of allergic reactions and might represent a useful tool for the treatment of allergic diseases.

Research over the past few years has identified essential roles for galectins, particularly Gal-1, in tolerance mechanisms that operate at the fetomaternal interface (123). Gal-1 is present in the female reproductive tract and is significantly upregulated during pregnancy (31, 32, 123, 124). In human placenta, Gal-1 is expressed by various cell types primarily regulated by progesterone and proinflammatory cytokines (32, 123).

In a model of stress-induced pregnancy failure (31), Lgals1^−/− mice showed higher rates of fetal loss compared with their WT counterparts in allogeneic, but not syngeneic, matings. Administration of Gal-1 prevented fetal loss and restored tolerance in vivo (31). Accordingly, human uterine NK cells inhibited the viability of decidual T cells via glycosylation-dependent Gal-1–mediated mechanisms (125). Moreover, transcriptional activity of NF-κB was altered by Gal-1 in human decidual cells, limiting the production of IL-6 (126). Mechanistically, Gal-1 conferred immune privilege to human trophoblast cells by limiting T cell viability, dampening Th1-type cytokines, and favoring expansion of Tregs (32). In line with these findings, patients with recurrent pregnancy loss had considerably lower levels of circulating Gal-1 and a higher frequency of anti–Gal-1 autoantibodies compared with sera from fertile women (32). Finally, other studies suggested that Gal-1 contributes to immunoregulation, placentation, and fetal growth mediated by uterine mast cells (127). Altogether, these findings support a protective role for Gal-1 in immune tolerance at the fetomaternal interface.

Immunosuppressive pathways that promote resolution of inflammation may be co-opted by cancer cells or their adjoining microenvironment to thwart antitumor responses (128). Using mouse melanoma models and human patient samples, we identified an essential role for Gal-1 as a mediator of tumor-immune escape (42). This effect was confirmed by disruption of Gal-1 ligands in vivo following administration of a metabolic inhibitor of LacNAc biosynthesis, which restrained tumor progression by stimulating antitumor immunity (129). Further studies demonstrated that Gal-1 also confers immune privilege to classical Hodgkin lymphoma by favoring a nonproductive immune infiltrate dominated by Th2 cells and Foxp3⁺ Tregs (130). Interestingly, in classical Hodgkin lymphoma and posttransplant lymphoproliferative disorders, two hematological malignancies associated with EBV infection, Gal-1 expression was driven by an enhancer of the AP-1 transcription factor (130, 131), suggesting that oncogenic viruses may usurp the Gal-1 pathway to promote immune escape. Likewise, Kaposi’s sarcoma–associated herpes virus induced Gal-1 expression, which coupled angiogenesis, inflammation, and tumorigenesis in Kaposi’s sarcoma (43). Remarkably, co-option of the Gal-1–glycan pathway as a major immune-evasive program was demonstrated in a number of tumor models, including lung, breast, pancreatic, and ovarian carcinoma, as well as glioblastoma, neuroblastoma, and T cell lymphoma (19, 26, 28, 29, 42–44, 69, 132–136). The mechanisms underlying these immune-inhibitory effects vary significantly among different tumor types and include expansion of Tregs, differentiation of tolerogenic DCs, induction of T cell apoptosis, promotion of a Th2 cytokine profile, deactivation of macrophages, T cell exclusion, and inhibition of NK cell function (4). Interestingly, reinvigoration of antitumor responses observed upon disruption of galectin-specific ligands (i.e., complex branched N-glycans) was even more impressive than that observed in response to Gal-1 blockade (19), suggesting the contribution of other members of the galectin family to tumor-driven immunosuppression. Accordingly, Gal-3 promotes T cell dysfunction by directly interacting with LAG-3 or by distancing the TCR from CD8 molecules (15, 137), whereas Gal-9 limited antitumor immunity by engaging Dectin-1 on tumor-associated macrophages (16).

Notably, although Gal-1 is typically upregulated in cancer cells, in some tumor types, immune or stromal cells appear to be the main Gal-1 source. Particularly in ovarian cancer models, γδ T lymphocytes and myeloid-derived suppressor cells emerge as major Gal-1 producers, linking TLR5-dependent inflammation, systemic immunosuppression, and tumor progression (29). Moreover, this lectin is preferentially expressed in a subset of Satb1-driven Zbtb46⁺ immunosuppressive DCs that infiltrate ovarian tumors (28). Furthermore, in human chronic lymphocytic leukemia, Gal-1 is mainly secreted by nurse-like myeloid cells and macrophages, facilitating establishment of appropriate tumorigenic niches (81). Finally, Gal-1 expression, driven by hypoxic microenvironments, has been established as a link between tumor angiogenesis and immunosuppression (43) and as a key determinant of sensitivity to different anticancer therapies, including those targeting vascular endothelial growth factor (19, 138) and CD20 (139). Thus, blockade of Gal-1 or disruption of its specific glycosylated ligands may contribute to reduce tumor progression by attenuating immunosuppression and counteracting aberrant angiogenesis.

Mechanisms that promote resolution of inflammation may hinder orchestration of antimicrobial responses, but they may also counteract pathogen-induced immunopathology. Moreover, microbes may co-opt inhibitory pathways to subvert host protective immunity (1). Recently we found that Gal-1–driven tolerogenic circuits can repress protective immunity during infection with Yersinia enterocolitica, an enteropathogenic bacterium, by targeting local immunity, including NO production, NF-κB activation, and TNF synthesis, as well as systemic Th1 and Th17 responses (38). Similarly, in a model of Trypanosoma cruzi infection, Gal-1 fueled the activation of immunoregulatory circuits that hindered antiparasite immunity, particularly those involving differentiation of tolerogenic DCs and Tregs (37). Moreover, in an in vitro model of Trichomonas vaginalis infection, Gal-1 inhibited recruitment of phagocytes by suppressing central chemokines, primarily IL-8, MIP-3α, and RANTES (140). Thus, targeting the Gal-1–glycan axis may contribute to reinforce host protective immunity by counteracting local and systemic immunosuppressive programs. However, as mentioned above, administration of Gal-1 ameliorated corneal immunopathology induced by Pseudomonas aeruginosa by suppressing Th17 responses (36). Finally, Gal-1, as well as other galectins, have been proposed to serve as pathogen-recognition receptors that could positively or negatively regulate inflammatory responses by sensing glycans on the surface of pathogenic microbes (141). Thus, Gal-1 may play multifaceted roles during infection by subverting antimicrobial responses, orchestrating host immunity, or curbing pathogen-driven immunopathology.

Excessive inflammation is widely appreciated as a critical component in almost all diseases, including autoimmune, neurodegenerative, and metabolic diseases, as well as infection, asthma, and cancer (2). Gal-1 has emerged as a potent homeostatic signal that, together with other anti-inflammatory mediators and RAMPS, controls unresolved inflammation and limits immunopathology while hindering antimicrobial and antitumor responses. The mechanisms underlying these effects range from modulation of macrophage polarization, inhibition of eosinophil and neutrophil trafficking, induction of tolerogenic DCs, expansion of Tregs, and modulation of T cell function to control of cytokine synthesis (Fig. 1). These broad immunoregulatory activities open novel therapeutic opportunities for reprogramming innate and adaptive immunity in a wide range of inflammatory conditions. Although Gal-1–targeted therapies, using neutralizing anti–Gal-1 mAb, glycoamines, or synthetic peptides, have been designed and validated in preclinical models to reinforce antitumor and antimicrobial immunity, Gal-1–agonistic drugs for limiting unresolved inflammation in diverse inflammation conditions are anticipated to be released (6, 19, 43, 131, 142). However, before Gal-1–based therapeutic agents will be embraced, several questions remain to be addressed: Do other members of the galectin family play compensatory roles in response to Gal-1 blockade? Why does Gal-1 bind to a preferential set of glycosylated receptors even though glycan ligands are ubiquitously expressed in a wide range of receptors? Do protein–protein interactions play any role in Gal-1 receptor association that could be targeted as an alternative therapeutic approach? What is the therapeutic advantage of blocking individual galectins instead of targeting a set of galectins with similar or complementary regulatory activities? Thus, although evidence presented in this article supports the multiple regulatory functions of Gal-1, its possible mechanisms of action, and its broad therapeutic potential, progress made thus far might represent only the “tip of an iceberg” within the exciting field of glycoimmunology, with more mechanistic insights and therapeutic approaches awaiting future discovery.

The authors have no financial conflicts of interest.