Among the different proteoglycans expressed by mammals, serglycin is in most immune cells the dominating species. A unique property of serglycin is its ability to adopt highly divergent structures, because of glycosylation with variable types of glycosaminoglycans when expressed by different cell types. Recent studies of serglycin-deficient animals have revealed crucial functions for serglycin in a diverse array of immunological processes. However, its exact function varies to a large extent depending on the cellular context of serglycin expression. Based on these findings, serglycin is emerging as a structural and functional chameleon, with radically different properties depending on its exact cellular and immunological context.

Proteoglycans are built up of a protein part, the so-called core protein, which is glycosylated with sulfated and thereby negatively charged glycosaminoglycans (GAGs). Proteoglycans can be roughly divided into cell surface-associated (e.g., syndecans, glypicans) and extracellular species (e.g., decorin, aggrecan, perlecan), but they can also be found within intracellular secretory compartments, serglycin being the most notable example (1).

The relatively recent generation of serglycin−/− mice has revealed a wide impact of serglycin on the functional properties of numerous immune cells. Intriguingly, though, the exact function of serglycin varies extensively between different serglycin-expressing cell types. A likely explanation for this is its remarkably variable glycosylation pattern in different cells, ranging from glycosylation with highly sulfated GAGs of heparin type in connective tissue type mast cells (MCs) to low-sulfated chondroitin sulfate (CS) chains in, for example, T lymphocytes. Hence serglycin can be regarded as a structural and functional chameleon, being able to dynamically and radically change its structural and functional characteristics depending on biological context.

The existence of a compound with the characteristics of serglycin was first indicated from studies on heparin in rat skin, where a compound denoted “macromolecular heparin” was identified (2). Later, this type of compound was shown to be present also in rat peritoneal MCs (3, 4) and was subsequently classified as a proteoglycan (5). Moreover, it was shown that the proteoglycan was protease resistant and rich in Ser and Gly residues (5).

Among all proteoglycans, serglycin was the first to be identified at the cDNA level and was named so because of a characteristic, extensive stretch of Ser-Gly repeats found in the serglycin core protein of all species (610). The Ser residues of these repeats constitute the GAG attachment sites. Because of the close proximity of such sites, serglycin is densely substituted with GAG chains. Notably, this dense clustering of GAGs provides the basis for the strong protease resistance of serglycin (25, 11) and may also have additional functional implications, for example, to enable tight packaging of large amounts of GAG-binding compounds within a small volume.

N-terminal sequencing of serglycin isolated from conditioned media of two different monocyte cell lines revealed extensive processing of the core protein N terminus (12, 13). However, it is not known whether the N-terminal processing of serglycin has any functional consequence.

The type and extent of sulfation of GAG chains attached to the serglycin core protein varies extensively between cell types (Fig. 1, Table I). The most well-known serglycin-associated GAG is heparin, a GAG species with a remarkably high extent of sulfation, which is expressed only in connective tissue type MCs (Fig. 1, Table I). In several cells found in the circulation, such as lymphocytes, platelets, and monocytes, serglycin is substituted with lower sulfated chondroitin 4-sulfate (CS-4) chains (Fig. 1, Table I) (29). However, several hematopoietic cells, including mucosal type MCs, bone marrow-derived MCs, and activated monocytes and macrophages, express CS with a higher extent of sulfation (“oversulfated CS”), either of CS-E or CS-diB type (Fig. 1, Table I) (30, 31). Notably, serglycin isolated from primary murine macrophages has also been shown to contain heparan sulfate, a GAG type with the same carbohydrate backbone structure as heparin but having a lower sulfate content (Fig. 1, Table I) (26). Interestingly, the GAG repertoire of serglycin also includes hybrid proteoglycans, carrying both heparin and CS chains (32), adding to its structural complexity.

FIGURE 1.

Different serglycin GAG structures. Orange represents iduronic acid; green represents glucuronic acid; blue represents N-acetylgalactosamine; gray represents N-acetylglucosamine.

FIGURE 1.

Different serglycin GAG structures. Orange represents iduronic acid; green represents glucuronic acid; blue represents N-acetylgalactosamine; gray represents N-acetylglucosamine.

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Table I.
Properties and functions of serglycin in different cell types
Cell TypeGAG ComponentExtent of GAG SulfationPredominant FateFunctionReferences
MCs (connective tissue type) Heparin +++ Storage/regulated secretion Promotes storage of proteases, histamine, serotonin; regulation of apoptosisa 1416  
 CS-E ++    
MCs (mucosal type) CS-4 Storage/regulated secretion Promotes storage of proteasesa 17  
 CS-E ++    
 CS-diB ++    
CTLs CS-4 Storage/regulated secretion Promotes storage of granzyme B; regulation of CD8+ T cell contractiona 1820  
Endothelial cells CS-4 Constitutive secretion (apical) Secretion of CXCL1 21  
Platelets CS-4 Storage/regulated secretion Promotes storage of CXCL4, CXCL7, PDGF; promotes platelet aggregationa 22  
Neutrophils CS-4 Storage/regulated secretion Promotes storage of elastasea 23, 24  
Eosinophils CS-4 Storage/regulated secretion ND 25  
 CS-E (minor) ++    
Macrophages CS-4 Constitutive secretion Regulation of cytokine secretiona 26  
 CS-E ++    
 Heparan sulfate    
Multiple myeloma cells CS-4 Constitutive secretion Inhibition of bone mineralization 27  
Nasopharyngeal carcinoma ND ND Constitutive secretion Promotion of cell migration, metastasis 28  
Cell TypeGAG ComponentExtent of GAG SulfationPredominant FateFunctionReferences
MCs (connective tissue type) Heparin +++ Storage/regulated secretion Promotes storage of proteases, histamine, serotonin; regulation of apoptosisa 1416  
 CS-E ++    
MCs (mucosal type) CS-4 Storage/regulated secretion Promotes storage of proteasesa 17  
 CS-E ++    
 CS-diB ++    
CTLs CS-4 Storage/regulated secretion Promotes storage of granzyme B; regulation of CD8+ T cell contractiona 1820  
Endothelial cells CS-4 Constitutive secretion (apical) Secretion of CXCL1 21  
Platelets CS-4 Storage/regulated secretion Promotes storage of CXCL4, CXCL7, PDGF; promotes platelet aggregationa 22  
Neutrophils CS-4 Storage/regulated secretion Promotes storage of elastasea 23, 24  
Eosinophils CS-4 Storage/regulated secretion ND 25  
 CS-E (minor) ++    
Macrophages CS-4 Constitutive secretion Regulation of cytokine secretiona 26  
 CS-E ++    
 Heparan sulfate    
Multiple myeloma cells CS-4 Constitutive secretion Inhibition of bone mineralization 27  
Nasopharyngeal carcinoma ND ND Constitutive secretion Promotion of cell migration, metastasis 28  
a

As indicated by studies of serglycin−/− animals.

PDGF, platelet-derived growth factor.

The size of serglycin may vary depending on the number of GAG chains attached to the protein core and because of variations in chain length of the attached GAGs (29). Of note, an early study in eosinophils showed that the length of the serglycin CS-4/CS-E chains increased after stimulation with IL-3 or GM-CSF (25), suggesting that serglycin may undergo profound structural alterations in response to immunological signals. Most likely, such structural dynamics will influence the functional properties of serglycin with regard to storage and/or release of bound compounds. As an example, Wistar–Furth rats have a platelet phenotype with similarities to the human gray platelet syndrome, proposed to be due to the abnormally low size of the serglycin proteoglycans present in the α-granules (33).

Serglycin was originally regarded as a hematopoietic cell proteoglycan species (29), being highly expressed by several hematopoietic cell types, such as MCs, NK cells, CTLs, platelets, and macrophages (18, 22, 26, 34). However, serglycin is also expressed by a number of nonhematopoietic cell types, including endothelial cells (21), chondrocytes (35), and smooth muscle cells (36). Moreover, high levels of serglycin expression have been detected in various transformed cell types, such as multiple myeloma cells (27), and in highly metastatic carcinomas (28). With the use of an anti-serglycin Ab, the serglycin core protein has been detected in spleen, lymph nodes, and bone marrow (3739).

Serglycin expression has been most thoroughly studied in MCs. An early study suggested that MCs have a high capacity for serglycin expression as compared with other cell types (40). In agreement with this notion, serglycin is strongly induced during the process of MC differentiation from bone marrow stem cells (41). Interestingly, the expression of sulfotransferases needed to synthesize CS-E was upregulated in tandem, whereas enzymes involved in heparin synthesis were expressed later in the differentiation process (41). Furthermore, MC activation, leading to secretion of granule content (including serglycin), induced serglycin mRNA expression and, again, expression of CS-E–related enzymes. In contrast, heparin-synthesizing enzymes were downregulated after activation (41). These studies suggest dynamic regulation of serglycin expression and, in particular, differences in the regulation of distinct sulfotransferases that most likely reflect a temporal regulation with importance for de novo synthesis of distinct granule components interacting with serglycin.

Serglycin expression has also been studied in several cell lines used as model systems for hematopoietic differentiation. For example, megakaryocytic differentiation is associated with increased serglycin expression (42, 43), whereas treatment of leukemic cell lines with PMA decreased the expression of serglycin mRNA (44). During myeloblast differentiation, increased serglycin expression was shown to coincide with granule biogenesis (45), whereas, in contrast, serglycin expression is downregulated during promyelocyte differentiation into mature neutrophils (23).

The basis for the variable serglycin expression patterns in different hematopoietic lineages is not known, although limited evidence suggests that different expression of regulatory factors (46) or differences in DNase I hypersensitivity sites in the serglycin gene may explain differences in expression between cell types (47).

Ever since the identification of serglycin in MC secretory granules, a role for serglycin in promoting secretory granule storage processes has been proposed (7, 48). Indeed, when the gene for serglycin was inactivated, severely impaired storage of a number of granule-localized proteases (chymases, tryptases, and carboxypeptidase A) was seen in MCs (14, 17). Importantly, the levels of mRNAs coding for the corresponding proteases were not altered in serglycin−/− cells, suggesting effects on storage rather than on mRNA expression. It was also demonstrated that histamine and serotonin storage in MCs relies strongly on serglycin (15). Notably, the storage defects seen in serglycin−/− MCs are similar to those seen in MCs that lack N-deacetylase/N-sulfotransferase 2, an enzyme crucial for sulfation of heparin, heparin being the dominant GAG of serglycin in connective tissue type MCs (49, 50). Hence the storage of the MC granule proteases and histamine/serotonin is critically dependent on the high anionic charge imposed by the sulfation of the heparin chains of serglycin. Collectively, these data strongly suggest that serglycin promotes granular storage through electrostatic interaction between the sulfated GAG side chains of serglycin and basically charged regions of secretory granule components.

Considering the vast impact of serglycin on MC granule storage, it may be expected that serglycin has an analogous role in other serglycin-expressing, secretory granule-containing cell types. Indeed, it was found that serglycin was crucial for mediating the storage of granzyme B in CTLs (18). However, serglycin did not affect the storage of either granzyme A or perforin, suggesting that serglycin selectively promotes the storage of certain granular compounds, whereas others are stored independently of serglycin (18). Possibly, the storage of granzyme A, which is a highly basic protein and thus likely to depend on interactions with anionic partners for storage, may depend on interactions with proteoglycan types other than serglycin. In line with such a scenario, CTLs are known to express proteoglycans of glypican and syndecan type (18). Also, neutrophils have been shown to express serglycin, but only at early stages of cellular maturation (23, 51). Nevertheless, serglycin was shown to be essential for storage of elastase in the azurophil granules of neutrophils (24). In contrast, the storage of other azurophil granule compounds, including cathepsin G and proteinase 3, was unaffected by the absence of serglycin (24). In platelets, the absence of serglycin has multiple effects, including severely defective storage of CXCL4, CXCL7, and platelet-derived growth factor (22).

Together, it is now established that a major function of serglycin in immune cells is to allow the storage of large amounts of various compounds aimed for regulated secretion. Thus, the presence of serglycin enables the rapid secretion of preformed immunoactive substances at early stages of, for example, an inflammatory reaction, and it is therefore reasonable to assume that the biological impact of serglycin is most profound in the initial stages of an immunological process.

It is notable that the impact of serglycin on CTLs, platelets, and neutrophils is somewhat less dramatic than its effects on MCs. One plausible explanation for this may be that the GAG chains of CTL, neutrophil, and platelet serglycin are relatively low-sulfated in comparison with the heparin chains of MC serglycin. Thus, by virtue of a limited extent of sulfation, serglycin expressed by CTLs, neutrophils, and platelets may have a lower impact on cellular homeostasis as compared with the dramatic effects of serglycin seen in MCs.

A striking finding is that the absence of serglycin in MCs results in a complete absence of metachromatic staining (14). At first glance, this may be interpreted as an absence of secretory granules, but an ultrastructural examination revealed that granules are, in fact, present in serglycin−/− MCs, in approximately equal numbers and of similar size as in wild type (WT) controls (17, 52). However, the granule morphology was dramatically different in WT as opposed to serglycin−/− cells, with WT granules containing typical dense core regions interspersed with electron translucent areas, whereas serglycin−/− granules lack dense core formation and instead contain evenly distributed amorphous material throughout the entire granules (17). Notably, the absence of serglycin does not lead to defects in the ability of MCs to degranulate (52). A dependence on serglycin for dense core formation was also seen in the cytolytic granules of CTLs (18), whereas, in contrast, no morphological effects of serglycin deficiency were seen in either macrophages (26) or neutrophils (24). In platelets, the absence of serglycin was associated with formation of unusual cigar-like membrane inclusions, reminiscent of the pathology seen in certain platelet-related disorders (22).

The variable effect of serglycin on the morphology of different cell types is most likely reflected by the differential fate of serglycin in these cell types. For example, the lack of impact of serglycin deficiency on macrophage morphology is most likely related to the finding that serglycin is not retained intracellularly by macrophages (26), and the lack of effects on neutrophil morphology could be explained by the absence of serglycin in granules of mature neutrophils (23, 51). In contrast, the dramatic effect of serglycin deficiency on MCs is well in line with the high expression of the serglycin gene in MCs and with the large amounts of serglycin found in MC secretory granules.

Serglycin is secreted either constitutively or in a regulated manner (Table I), the latter being exemplified by MC degranulation. However, also in cells that secrete serglycin constitutively, increased serglycin secretion can be induced by exposure to various agents, such as TNF (53) and LPS (26), suggesting that these cells can adapt their serglycin expression according to external inflammatory stimuli.

The function of secreted serglycin is intriguing. One major function is probably to act as a vehicle for the extracellular delivery of those compounds that are stored in complex with serglycin within cells (Fig. 2, Table I). After secretion, some of the serglycin-associated compounds, for example, histamine, will be released from serglycin because of the increased pH of the extracellular milieu, whereas others may remain attached also after exocytosis (Fig. 2). An association with serglycin after secretion may, in fact, have considerable functional consequences. For example, serglycin could confer protection toward proteolytic attack, facilitate presentation of substrates to serglycin-bound proteases, mediate transport of compounds to other anatomical sites (55), or aid in the presentation of cargo molecules (e.g., chemokines) (21, 22, 56) to their target cells (Fig. 2). It is also possible that secreted serglycin may act as a scavenger that binds to and sequesters inflammatory compounds present in the extracellular environment, for example, GAG-binding chemokines, thereby being an immunomodulator. Secreted serglycin has also been shown to bind to cell surfaces (27, 37), for example, by interacting with CD44 (Fig. 2) (37).

FIGURE 2.

Functions of serglycin. Depending on cell type, serglycin is either constitutively secreted or transported to secretory vesicles (granules) for subsequent regulated secretion. Several types of compounds are bound to serglycin and are released in complexes with serglycin: 1) serglycin-bound proteases may rely on serglycin for optimal presentation of substrates (54); 2) serglycin may facilitate the transport of, for example, chemokines to their target cells and assist in their presentation to receptors (21, 22, 55, 56); 3) after secretion, serglycin may interact with cell surfaces, either through CD44 (37) or via other partners; 4) some of the serglycin-bound compounds will be detached from serglycin after secretion, whereas others remain attached to serglycin; and 5) upon damage to secretory granules, serglycin–protease complexes are released into the cytosol and may provoke apoptosis (16).

FIGURE 2.

Functions of serglycin. Depending on cell type, serglycin is either constitutively secreted or transported to secretory vesicles (granules) for subsequent regulated secretion. Several types of compounds are bound to serglycin and are released in complexes with serglycin: 1) serglycin-bound proteases may rely on serglycin for optimal presentation of substrates (54); 2) serglycin may facilitate the transport of, for example, chemokines to their target cells and assist in their presentation to receptors (21, 22, 55, 56); 3) after secretion, serglycin may interact with cell surfaces, either through CD44 (37) or via other partners; 4) some of the serglycin-bound compounds will be detached from serglycin after secretion, whereas others remain attached to serglycin; and 5) upon damage to secretory granules, serglycin–protease complexes are released into the cytosol and may provoke apoptosis (16).

Close modal

Froelich et al. (19, 57) introduced the possibility that serglycin may have a role in apoptosis by showing that serglycin binds to granzyme B (57) and that serglycin can act as a vehicle for delivering granzyme B from CTLs into target cells (19). In agreement with this notion, the absence of serglycin causes impaired storage of granzyme B both in Con A-induced CTLs (18) and in CD8+ T lymphocytes and NK cells from mice infected with lymphocytic choriomeningitis virus (20).

More recently, cell-intrinsic serglycin has been implicated in the control of MC apoptosis. MCs synthesize and store vast amounts of fully active, serglycin-dependent proteases in their secretory granules (14, 17). Damage to the granules, for example, by various types of cellular stress, will thus cause leakage of large amounts of active proteases into the cytosol (Fig. 2), and these proteases may have the potential to cause apoptosis by proteolytic activation of proapoptotic compounds present in the cytosol. Indeed, MCs were shown to be highly sensitive to apoptosis induced by secretory granule destabilization, and moreover, serglycin−/− MCs and MCs that lack individual serglycin-dependent proteases were less sensitive than were WT cells (16). A striking finding was that serglycin−/− cells, when eventually undergoing cell death, die preferentially by necrosis rather than by apoptosis (16). Hence these findings implicate serglycin as a new player in the regulation of apoptosis.

Considering the many reported effects of serglycin deficiency on immune cells, it may be expected that serglycin−/− mice are immunocompromised. Indeed, it has been shown that serglycin−/− mice have a reduced capacity to clear Klebsiella pneumoniae infection, possibly linked to the defective storage of elastase in serglycin−/− neutrophils (24). Further, serglycin has a role in the early neutrophil recruitment during Toxoplasma gondii infection (58), and it is also notable that serglycin was one of the genes showing the highest extent of upregulation during severe bacteria-mediated uterine disease (59).

Based on the demonstrated impact of serglycin on granzyme B in CTLs, it may be expected that serglycin has a role during virus infection. It was therefore somewhat surprising that serglycin−/− mice were able to clear lymphocytic choriomeningitis virus infection as efficiently as were WT animals (20). However, an intriguing finding was that the contraction of the CD8+ immune response was markedly delayed in serglycin−/− mice as compared with WT controls, and this could be attributed to sustained proliferation of the CD8+ cells (20). Hence, although not affecting the actual ability to clear virus infection, serglycin appears to control the magnitude and durability of the immune response.

An observation in line with these findings is that aging serglycin−/− mice spontaneously develop a massive enlargement of multiple lymphoid tissues, including spleen, BALT, and Peyer’s patches (60), suggesting that serglycin has functions in maintaining homeostasis of the body’s immune cell populations, for example, through effects on proliferation, apoptosis, or both.

On a different angle, it was recently shown that serglycin isolated from multiple myeloma cells can inhibit both the classical and lectin pathway of complement, through direct effects on C1q and mannose-binding lectin, respectively (61). These findings support the earlier reported ability of serglycin-like proteoglycans to inhibit complement activation (62). Finally, a recent study indicates that serglycin (heparin) released from MCs into the circulation may have proinflammatory properties mediated via activation of bradykinin (63).

In support of a role for serglycin in malignancies, serglycin was identified as the main proteoglycan synthesized by multiple myeloma cells (27). Serglycin was secreted to the medium but, interestingly, was also recovered on the cell surface, attached through its GAG chains. Further, multiple myeloma-derived serglycin interfered with bone mineralization, providing a possible explanation for the osteoporosis commonly seen in multiple myeloma patients. In line with these findings, serglycin is highly expressed by leukemic blasts of patients with acute myeloid leukemia, but not in bone marrow from patients with acute lymphoblastic leukemia. Moreover, it was demonstrated that plasma levels of serglycin were higher in acute myeloid leukemia than in acute lymphoblastic leukemia patients (38), suggesting that serglycin can be used as a biomarker to distinguish between these two malignancies.

In a more recent study, Li et al. (28) showed that nasopharyngeal carcinoma cells expressed high levels of serglycin, and that the levels of serglycin expression correlated with the metastatic potential of different nasopharyngeal carcinoma cell clones. Moreover, knockdown of serglycin expression reduced the motility and metastatic potential of the cells in vivo; conversely, overexpression of serglycin in poorly metastatic clones caused higher motility and increased metastatic potential (28). Together, these findings implicate serglycin as a novel prognostic marker and a pathogenic factor in malignancies.

Among all GAG types, heparin is the most well-known, mainly because of its wide use as a blood anticoagulant. As heparin is synthesized exclusively onto the serglycin core protein (in MCs), it may be expected that serglycin-deficient mice suffer from thrombotic disorders. However, no such defects have been noted, thus arguing against heparin having a physiological role in the control of blood coagulation. In fact, serglycin expressed by platelets (containing CS side chains) rather appears to have an opposing, procoagulant function in vivo, by promoting platelet aggregation (22).

As described in this review, serglycin is emerging as the dominant proteoglycan species expressed by immune cells. Further, it is now evident that serglycin has a major functional impact on processes of crucial importance for the immune system. However, several important aspects of serglycin function need to be addressed. One important issue is to further evaluate the role of serglycin in various disorders, in particular, those in which cells that express high levels of serglycin are implicated. Another critical issue is to determine the exact mechanism behind the immune-modulating role of serglycin in various settings. For example, given the implication of serglycin in a particular pathological setting, it will be important to determine whether this is attributable to serglycin expressed by a certain cell type. To accomplish this, we foresee the use of mice with conditionally inactivated serglycin expression. Another challenge for future research will be to evaluate whether serglycin can be used as biomarker for any particular disease and whether modulation of serglycin expression can be used as a therapeutic strategy.

This work was supported by Formas, the Swedish Research Council; King Gustaf V 80-Year Anniversary Fund; Torsten and Ragnar Söderberg Foundation; the Swedish Cancer Foundation; the Throne Holst Foundation; and South-Eastern Norway Regional Health Authority.

Abbreviations used in this article:

CS

chondroitin sulfate

CS-4

chondroitin 4-sulfate

GAG

glycosaminoglycan

MC

mast cell

WT

wild type.

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The authors have no financial conflicts of interest.