Serglycin: a Structural and Functional Chameleon with Wide Impact on Immune Cells

Serglycin: A Structural and Functional Chameleon with Wide Impact on Immune Cells

This information is current as Svein O. Kolset and Gunnar Pejler of September 28, 2021. J Immunol 2011; 187:4927-4933; ; doi: 10.4049/jimmunol.1100806 http://www.jimmunol.org/content/187/10/4927 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Serglycin: A Structural and Functional Chameleon with Wide Impact on Immune Cells Svein O. Kolset* and Gunnar Pejler† Among the different proteoglycans expressed by mam- where a compound denoted “macromolecular heparin” was mals,serglycinisinmostimmunecellsthedominatingspe- identified (2). Later, this type of compound was shown to be cies. A unique property of serglycin is its ability to adopt present also in rat peritoneal MCs (3, 4) and was subsequently highly divergent structures, because of glycosylation with classified as a proteoglycan (5). Moreover, it was shown that variable types of glycosaminoglycans when expressed by the proteoglycan was protease resistant and rich in Ser and different cell types. Recent studies of serglycin-deficient Gly residues (5). animals have revealed crucial functions for serglycin in a Among all proteoglycans, serglycin was the first to be diverse array of immunological processes. However, its identified at the cDNA level and was named so because of Downloaded from exact functionvariestoalargeextentdependingonthecel- a characteristic, extensive stretch of Ser-Gly repeats found in lular context of serglycin expression. Based on these find- the serglycin core protein of all species (6–10). The Ser resi- ings, serglycin is emerging as a structural and functional dues of these repeats constitute the GAG attachment sites. chameleon, with radically different properties depending Because of the close proximity of such sites, serglycin is on its exact cellular and immunological context. The densely substituted with GAG chains. Notably, this dense http://www.jimmunol.org/ Journal of Immunology, 2011, 187: 4927–4933. clustering of GAGs provides the basis for the strong protease resistance of serglycin (2–5, 11) and may also have additional functional implications, for example, to enable tight packag- roteoglycans are built up of a protein part, the so- ing of large amounts of GAG-binding compounds within a called core protein, which is glycosylated with sul- small volume. P fated and thereby negatively charged glycosamino- N-terminal sequencing of serglycin isolated from condi- glycans (GAGs). Proteoglycans can be roughly divided into tioned media of two different monocyte cell lines revealed cell surface-associated (e.g., syndecans, glypicans) and extra- extensive processing of the core protein N terminus (12, 13). cellular species (e.g., decorin, aggrecan, perlecan), but they However, it is not known whether the N-terminal processing by guest on September 28, 2021 can also be found within intracellular secretory compartments, of serglycin has any functional consequence. serglycin being the most notable example (1). 2 2 The type and extent of sulfation of GAG chains attached to The relatively recent generation of serglycin / mice has the serglycin core protein varies extensively between cell types revealed a wide impact of serglycin on the functional prop- (Fig. 1, Table I). The most well-known serglycin-associated erties of numerous immune cells. Intriguingly, though, the GAG is heparin, a GAG species with a remarkably high extent exact function of serglycin varies extensively between different serglycin-expressing cell types. A likely explanation for this is of sulfation, which is expressed only in connective tissue type its remarkably variable glycosylation pattern in different cells, MCs (Fig. 1, Table I). In several cells found in the circulation, ranging from glycosylation with highly sulfated GAGs of such as lymphocytes, platelets, and monocytes, serglycin is heparin type in connective tissue type mast cells (MCs) to substituted with lower sulfated chondroitin 4-sulfate (CS-4) low-sulfated chondroitin sulfate (CS) chains in, for example, chains (Fig. 1, Table I) (29). However, several hematopoietic T lymphocytes. Hence serglycin can be regarded as a struc- cells, including mucosal type MCs, bone marrow-derived MCs, tural and functional chameleon, being able to dynamically and activated monocytes and macrophages, express CS with and radically change its structural and functional character- a higher extent of sulfation (“oversulfated CS”), either of istics depending on biological context. CS-E or CS-diB type (Fig. 1, Table I) (30, 31). Notably, serglycin isolated from primary murine macrophages has Structural diversity of serglycin also been shown to contain heparan sulfate, a GAG type with The existence of a compound with the characteristics of ser- the same carbohydrate backbone structure as heparin but glycin was first indicated from studies on heparin in rat skin, having a lower sulfate content (Fig. 1, Table I) (26). Inter-

*Department of Nutrition, University of Oslo, 0316 Oslo, Norway; and †Department Biochemistry, BMC, Box 575, 75123 Uppsala, Sweden (G.P.) or Department of Nu- of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, trition, University of Oslo, Box 1046, Blindern, 0316 Oslo, Norway (S.O.K.). E-mail 75123 Uppsala, Sweden addresses: [email protected] (G.P.) and [email protected] (S.O.K.) Received for publication June 8, 2011. Accepted for publication August 18, 2011. Abbreviations used in this article: CS, chondroitin sulfate; CS-4, chondroitin 4-sulfate; GAG, glycosaminoglycan; MC, mast cell; WT, wild type. This work was supported by Formas, the Swedish Research Council; King Gustaf V 80-Year Anniversary Fund; Torsten and Ragnar So¨derberg Foundation; the Swedish Cancer Founda- Ó tion; the Throne Holst Foundation; and South-Eastern Norway Regional Health Authority. Copyright 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 Address correspondence and reprint requests to Gunnar Pejler or Svein O. Kolset, Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100806 4928 BRIEF REVIEWS: SERGLYCIN

FIGURE 1. Different serglycin GAG structures. Orange represents iduronic acid; green represents glu- curonic acid; blue represents N-ace- tylgalactosamine; gray represents N- acetylglucosamine. Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021 estingly, the GAG repertoire of serglycin also includes hybrid metastatic carcinomas (28). With the use of an anti-serglycin proteoglycans, carrying both heparin and CS chains (32), Ab, the serglycin core protein has been detected in spleen, adding to its structural complexity. lymph nodes, and bone marrow (37–39). The size of serglycin may vary depending on the number Serglycin expression has been most thoroughly studied in of GAG chains attached to the protein core and because of MCs. An early study suggested that MCs have a high capacity variations in chain length of the attached GAGs (29). Of note, for serglycin expression as compared with other cell types an early study in eosinophils showed that the length of the (40). In agreement with this notion, serglycin is strongly in- serglycin CS-4/CS-E chains increased after stimulation with duced during the process of MC differentiation from bone IL-3 or GM-CSF (25), suggesting that serglycin may undergo marrow stem cells (41). Interestingly, the expression of sul- profound structural alterations in response to immunological fotransferases needed to synthesize CS-E was upregulated in signals. Most likely, such structural dynamics will inﬂuence tandem, whereas enzymes involved in heparin synthesis were the functional properties of serglycin with regard to storage expressed later in the differentiation process (41). Further- and/or release of bound compounds. As an example, Wistar– more, MC activation, leading to secretion of granule content Furth rats have a platelet phenotype with similarities to the (including serglycin), induced serglycin mRNA expression human gray platelet syndrome, proposed to be due to the and, again, expression of CS-E–related enzymes. In contrast, abnormally low size of the serglycin proteoglycans present in heparin-synthesizing enzymes were downregulated after acti- the a-granules (33). vation (41). These studies suggest dynamic regulation of serglycin expression and, in particular, differences in the re- Regulation of serglycin expression gulation of distinct sulfotransferases that most likely reﬂect Serglycin was originally regarded as a hematopoietic cell a temporal regulation with importance for de novo synthesis proteoglycan species (29), being highly expressed by several of distinct granule components interacting with serglycin. hematopoieticcelltypes,suchasMCs,NKcells,CTLs, Serglycin expression has also been studied in several cell platelets, and macrophages (18, 22, 26, 34). However, ser- lines used as model systems for hematopoietic differentiation. glycin is also expressed by a number of nonhematopoietic cell For example, megakaryocytic differentiation is associated with types, including endothelial cells (21), chondrocytes (35), and increased serglycin expression (42, 43), whereas treatment of smooth muscle cells (36). Moreover, high levels of serglycin leukemic cell lines with PMA decreased the expression of expression have been detected in various transformed cell serglycin mRNA (44). During myeloblast differentiation, types, such as multiple myeloma cells (27), and in highly increased serglycin expression was shown to coincide with The Journal of Immunology 4929

Table I. Properties and functions of serglycin in different cell types

Extent of GAG Cell Type GAG Component Sulfation Predominant Fate Function References MCs (connective tissue type) Heparin +++ Storage/regulated Promotes storage of proteases, 14–16 secretion histamine, serotonin; regulation of apoptosisa CS-E ++ MCs (mucosal type) CS-4 + Storage/regulated Promotes storage of proteasesa 17 secretion CS-E ++ CS-diB ++ CTLs CS-4 + Storage/regulated Promotes storage of granzyme B; 18–20 secretion regulation of CD8+ T cell contractiona Endothelial cells CS-4 + Constitutive secretion (apical) Secretion of CXCL1 21 Platelets CS-4 + Storage/regulated Promotes storage of CXCL4, 22 secretion CXCL7, PDGF; promotes platelet aggregationa Neutrophils CS-4 + Storage/regulated Promotes storage of elastasea 23, 24 secretion

Eosinophils CS-4 + Storage/regulated ND 25 Downloaded from secretion CS-E (minor) ++ Macrophages CS-4 + Constitutive secretion Regulation of cytokine 26 secretiona CS-E ++ Heparan sulfate + Multiple myeloma cells CS-4 + Constitutive secretion Inhibition of bone 27 http://www.jimmunol.org/ mineralization Nasopharyngeal carcinoma ND ND Constitutive secretion Promotion of cell migration, 28 metastasis 2 2 aAs indicated by studies of serglycin / animals. PDGF, platelet-derived growth factor. granule biogenesis (45), whereas, in contrast, serglycin ex- action between the sulfated GAG side chains of serglycin and pression is downregulated during promyelocyte differentia- basically charged regions of secretory granule components. tion into mature neutrophils (23). Considering the vast impact of serglycin on MC granule by guest on September 28, 2021 The basis for the variable serglycin expression patterns in storage, it may be expected that serglycin has an analogous role different hematopoietic lineages is not known, although lim- in other serglycin-expressing, secretory granule-containing cell ited evidence suggests that different expression of regulatory types. Indeed, it was found that serglycin was crucial for factors (46) or differences in DNase I hypersensitivity sites in mediating the storage of granzyme B in CTLs (18). However, the serglycin gene may explain differences in expression be- serglycin did not affect the storage of either granzyme A or tween cell types (47). perforin, suggesting that serglycin selectively promotes the storage of certain granular compounds, whereas others are stored independently of serglycin (18). Possibly, the storage of Crucial role for serglycin in intracellular storage granzyme A, which is a highly basic protein and thus likely to Ever since the identification of serglycin in MC secretory depend on interactions with anionic partners for storage, may granules, a role for serglycin in promoting secretory granule depend on interactions with proteoglycan types other than storage processes has been proposed (7, 48). Indeed, when the serglycin. In line with such a scenario, CTLs are known to gene for serglycin was inactivated, severely impaired storage of express proteoglycans of glypican and syndecan type (18). a number of granule-localized proteases (chymases, tryptases, Also, neutrophils have been shown to express serglycin, but and carboxypeptidase A) was seen in MCs (14, 17). Impor- only at early stages of cellular maturation (23, 51). Never- tantly, the levels of mRNAs coding for the corresponding theless, serglycin was shown to be essential for storage of 2 2 proteases were not altered in serglycin / cells, suggesting elastase in the azurophil granules of neutrophils (24). In effects on storage rather than on mRNA expression. It was contrast, the storage of other azurophil granule compounds, also demonstrated that histamine and serotonin storage in including cathepsin G and proteinase 3, was unaffected by the MCs relies strongly on serglycin (15). Notably, the storage absence of serglycin (24). In platelets, the absence of serglycin 2 2 defects seen in serglycin / MCs are similar to those seen in has multiple effects, including severely defective storage of MCs that lack N-deacetylase/N-sulfotransferase 2, an enzyme CXCL4, CXCL7, and platelet-derived growth factor (22). crucial for sulfation of heparin, heparin being the dominant Together, it is now established that a major function of GAG of serglycin in connective tissue type MCs (49, 50). serglycin in immune cells is to allow the storage of large Hence the storage of the MC granule proteases and his- amounts of various compounds aimed for regulated secretion. tamine/serotonin is critically dependent on the high anionic Thus, the presence of serglycin enables the rapid secretion of charge imposed by the sulfation of the heparin chains of preformed immunoactive substances at early stages of, for serglycin. Collectively, these data strongly suggest that ser- example, an inflammatory reaction, and it is therefore rea- glycin promotes granular storage through electrostatic inter- sonable to assume that the biological impact of serglycin is 4930 BRIEF REVIEWS: SERGLYCIN most profound in the initial stages of an immunological pH of the extracellular milieu, whereas others may remain process. attached also after exocytosis (Fig. 2). An association with It is notable that the impact of serglycin on CTLs, platelets, serglycin after secretion may, in fact, have considerable and neutrophils is somewhat less dramatic than its effects on functional consequences. For example, serglycin could confer MCs. One plausible explanation for this may be that the GAG protection toward proteolytic attack, facilitate presentation chains of CTL, neutrophil, and platelet serglycin are relatively of substrates to serglycin-bound proteases, mediate transport low-sulfated in comparison with the heparin chains of MC of compounds to other anatomical sites (55), or aid in the serglycin. Thus, by virtue of a limited extent of sulfation, presentation of cargo molecules (e.g., chemokines) (21, 22, serglycin expressed by CTLs, neutrophils, and platelets may 56) to their target cells (Fig. 2). It is also possible that secreted have a lower impact on cellular homeostasis as compared with serglycin may act as a scavenger that binds to and sequesters the dramatic effects of serglycin seen in MCs. inflammatory compounds present in the extracellular envi- ronment, for example, GAG-binding chemokines, thereby Serglycin regulates secretory granule homeostasis being an immunomodulator. Secreted serglycin has also been A striking finding is that the absence of serglycin in MCs re- shown to bind to cell surfaces (27, 37), for example, by in- sults in a complete absence of metachromatic staining (14). At teracting with CD44 (Fig. 2) (37). first glance, this may be interpreted as an absence of secretory granules, but an ultrastructural examination revealed that Serglycin regulates apoptosis 2/2 granules are, in fact, present in serglycin MCs, in ap- Froelich et al. (19, 57) introduced the possibility that serglycin Downloaded from proximately equal numbers and of similar size as in wild type may have a role in apoptosis by showing that serglycin binds (WT) controls (17, 52). However, the granule morphology to granzyme B (57) and that serglycin can act as a vehicle for 2 2 was dramatically different in WT as opposed to serglycin / delivering granzyme B from CTLs into target cells (19). In cells, with WT granules containing typical dense core regions agreement with this notion, the absence of serglycin causes interspersed with electron translucent areas, whereas sergly- impaired storage of granzyme B both in Con A-induced CTLs 2 2 cin / granules lack dense core formation and instead contain (18) and in CD8+ T lymphocytes and NK cells from mice http://www.jimmunol.org/ evenly distributed amorphous material throughout the entire infected with lymphocytic choriomeningitis virus (20). granules (17). Notably, the absence of serglycin does not lead More recently, cell-intrinsic serglycin has been implicated in to defects in the ability of MCs to degranulate (52). A de- the control of MC apoptosis. MCs synthesize and store vast pendence on serglycin for dense core formation was also seen amounts of fully active, serglycin-dependent proteases in their in the cytolytic granules of CTLs (18), whereas, in contrast, secretory granules (14, 17). Damage to the granules, for ex- no morphological effects of serglycin deficiency were seen in ample, by various types of cellular stress, will thus cause either macrophages (26) or neutrophils (24). In platelets, the leakage of large amounts of active proteases into the cytosol

absence of serglycin was associated with formation of unusual (Fig. 2), and these proteases may have the potential to cause by guest on September 28, 2021 cigar-like membrane inclusions, reminiscent of the pathology apoptosis by proteolytic activation of proapoptotic com- seen in certain platelet-related disorders (22). pounds present in the cytosol. Indeed, MCs were shown to The variable effect of serglycin on the morphology of dif- be highly sensitive to apoptosis induced by secretory granule 2 2 ferent cell types is most likely reflected by the differential fate of destabilization, and moreover, serglycin / MCs and MCs serglycin in these cell types. For example, the lack of impact of that lack individual serglycin-dependent proteases were less serglycin deficiency on macrophage morphology is most likely sensitive than were WT cells (16). A striking finding was that 2 2 related to the finding that serglycin is not retained intracel- serglycin / cells, when eventually undergoing cell death, die lularly by macrophages (26), and the lack of effects on neu- preferentially by necrosis rather than by apoptosis (16). Hence trophil morphology could be explained by the absence of these findings implicate serglycin as a new player in the reg- serglycin in granules of mature neutrophils (23, 51). In con- ulation of apoptosis. trast, the dramatic effect of serglycin deficiency on MCs is well in line with the high expression of the serglycin gene in Impact of serglycin on immune regulation MCs and with the large amounts of serglycin found in MC Considering the many reported effects of serglycin deficiency 2 2 secretory granules. on immune cells, it may be expected that serglycin / mice are immunocompromised. Indeed, it has been shown that 2 2 Functions of secreted serglycin serglycin / mice have a reduced capacity to clear Klebsiella Serglycin is secreted either constitutively or in a regulated pneumoniae infection, possibly linked to the defective storage 2 2 manner (Table I), the latter being exemplified by MC de- of elastase in serglycin / neutrophils (24). Further, serglycin granulation. However, also in cells that secrete serglycin has a role in the early neutrophil recruitment during Toxo- constitutively, increased serglycin secretion can be induced by plasma gondii infection (58), and it is also notable that ser- exposure to various agents, such as TNF (53) and LPS (26), glycin was one of the genes showing the highest extent of suggesting that these cells can adapt their serglycin expression upregulation during severe bacteria-mediated uterine disease according to external inflammatory stimuli. (59). The function of secreted serglycin is intriguing. One major Based on the demonstrated impact of serglycin on granzyme function is probably to act as a vehicle for the extracellular B in CTLs, it may be expected that serglycin has a role during delivery of those compounds that are stored in complex with virus infection. It was therefore somewhat surprising that 2 2 serglycin within cells (Fig. 2, Table I). After secretion, some serglycin / mice were able to clear lymphocytic choriome- of the serglycin-associated compounds, for example, hista- ningitis virus infection as efficiently as were WT animals (20). mine, will be released from serglycin because of the increased However, an intriguing finding was that the contraction of the The Journal of Immunology 4931 Downloaded from http://www.jimmunol.org/

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). by guest on September 28, 2021

2 2 CD8+ immune response was markedly delayed in serglycin / interestingly, was also recovered on the cell surface, attached mice as compared with WT controls, and this could be at- through its GAG chains. Further, multiple myeloma-derived tributed to sustained proliferation of the CD8+ cells (20). serglycin interfered with bone mineralization, providing a Hence, although not affecting the actual ability to clear virus possible explanation for the osteoporosis commonly seen in infection, serglycin appears to control the magnitude and multiple myeloma patients. In line with these findings, ser- durability of the immune response. glycin is highly expressed by leukemic blasts of patients with An observation in line with these findings is that aging acute myeloid leukemia, but not in bone marrow from 2 2 serglycin / mice spontaneously develop a massive enlarge- patients with acute lymphoblastic leukemia. Moreover, it was ment of multiple lymphoid tissues, including spleen, BALT, demonstrated that plasma levels of serglycin were higher in and Peyer’s patches (60), suggesting that serglycin has func- acute myeloid leukemia than in acute lymphoblastic leukemia tions in maintaining homeostasis of the body’s immune cell patients (38), suggesting that serglycin can be used as a bio- populations, for example, through effects on proliferation, marker to distinguish between these two malignancies. apoptosis, or both. In a more recent study, Li et al. (28) showed that naso- On a different angle, it was recently shown that serglycin pharyngeal carcinoma cells expressed high levels of serglycin, isolated from multiple myeloma cells can inhibit both the and that the levels of serglycin expression correlated with the classical and lectin pathway of complement, through direct metastatic potential of different nasopharyngeal carcinoma effects on C1q and mannose-binding lectin, respectively (61). cell clones. Moreover, knockdown of serglycin expression re- These findings support the earlier reported ability of serglycin- duced the motility and metastatic potential of the cells in like proteoglycans to inhibit complement activation (62). Fi- vivo; conversely, overexpression of serglycin in poorly meta- nally, a recent study indicates that serglycin (heparin) released static clones caused higher motility and increased metastatic from MCs into the circulation may have proinflammatory potential (28). Together, these findings implicate serglycin as properties mediated via activation of bradykinin (63). a novel prognostic marker and a pathogenic factor in malignancies. Serglycin is implicated in cancer In support of a role for serglycin in malignancies, serglycin was Role of serglycin in blood coagulation identified as the main proteoglycan synthesized by multiple Among all GAG types, heparin is the most well-known, mainly myeloma cells (27). Serglycin was secreted to the medium but, because of its wide use as a blood anticoagulant. As heparin 4932 BRIEF REVIEWS: SERGLYCIN is synthesized exclusively onto the serglycin core protein (in 15. Ringvall, M., E. Ro¨nnberg, S. Wernersson, A. Duelli, F. Henningsson, M. Abrink, G. Garcıá-Faroldi, I. Fajardo, and G. Pejler. 2008. Serotonin and histamine storage MCs), it may be expected that serglycin-deficient mice suffer in mast cell secretory granules is dependent on serglycin proteoglycan. J. Allergy from thrombotic disorders. However, no such defects have Clin. Immunol. 121: 1020–1026. 16. Melo, F. R., I. Waern, E. Ro¨nnberg, M. A˚ brink, D. M. Lee, S. M. Schlenner, been noted, thus arguing against heparin having a physiolo- T. B. Feyerabend, H. R. Rodewald, B. Turk, S. Wernersson, and G. Pejler. 2011. A gical role in the control of blood coagulation. In fact, serglycin role for serglycin proteoglycan in mast cell apoptosis induced by a secretory granule- expressed by platelets (containing CS side chains) rather mediated pathway. J. Biol. Chem. 286: 5423–5433. 17. Braga, T., M. Grujic, A. Lukinius, L. Hellman, M. Abrink, and G. Pejler. 2007. appears to have an opposing, procoagulant function in vivo, Serglycin proteoglycan is required for secretory granule integrity in mucosal mast by promoting platelet aggregation (22). cells. Biochem. J. 403: 49–57. 18. Grujic, M., T. Braga, A. Lukinius, M. L. Eloranta, S. D. Knight, G. Pejler, and M. Abrink. 2005. Serglycin-deficient cytotoxic T lymphocytes display defective Conclusions secretory granule maturation and granzyme B storage. J. Biol. Chem. 280: 33411– As described in this review, serglycin is emerging as the 33418. 19. Metkar, S. S., B. Wang, M. Aguilar-Santelises, S. M. Raja, L. Uhlin-Hansen, dominant proteoglycan species expressed by immune cells. E. Podack, J. A. Trapani, and C. J. Froelich. 2002. Cytotoxic cell granule-mediated Further, it is now evident that serglycin has a major functional apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 16: 417–428. impact on processes of crucial importance for the immune 20. Grujic, M., J. P. Christensen, M. R. Sørensen, M. Abrink, G. Pejler, and system. However, several important aspects of serglycin A. R. Thomsen. 2008. Delayed contraction of the CD8+ T cell response toward function need to be addressed. One important issue is to lymphocytic choriomeningitis virus infection in mice lacking serglycin. J. Immunol. 181: 1043–1051. further evaluate the role of serglycin in various disorders, in 21. Meen, A. J., I. Øynebra˚ten, T. M. Reine, A. Duelli, K. Svennevig, G. Pejler, T. Jenssen, and S. O. Kolset. 2011. Serglycin is a major proteoglycan in polarized particular, those in which cells that express high levels of Downloaded from human endothelial cells and is implicated in the secretion of the chemokine serglycin are implicated. Another critical issue is to determine GROalpha/CXCL1. J. Biol. Chem. 286: 2636–2647. the exact mechanism behind the immune-modulating role of 22. Woulfe, D. S., J. K. Lilliendahl, S. August, L. Rauova, M. A. Kowalska, M. Abrink, G. Pejler, J. G. White, and B. P. Schick. 2008. Serglycin proteoglycan deletion serglycin in various settings. For example, given the implica- induces defects in platelet aggregation and thrombus formation in mice. 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