| 11. |
- Magnusson, Sofia E., et al.
(författare)
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Mast cell chymase contributes to the antibody response and the severity of autoimmune arthritis
- 2009
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 23:3, s. 875-882
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells are implicated in rheumatoid arthritis, but the mechanism by which they contribute to disease progression is not clarified. Here we investigated whether mouse mast cell protease-4 (mMCP-4), a chymase present in the mast cell secretory granule, contributes to experimental arthritis. Two models of arthritis were investigated in mMCP-4(+/+) and mMCP-4(-/-) DBA/1 mice: collagen-induced arthritis (CIA) was induced by immunization with collagen II (CII) in Freund's complete adjuvant, and a passive model of arthritis was induced by administration of anti-CII antibodies. The clinical scores were significantly reduced in the mMCP-4(-/-) animals as compared to mMCP-4(+/+) controls in both arthritis models. In CIA, the number of affected paws was lower in the CII-immunized mMCP-4(-/-) mice, with less cartilage destruction, pannus formation, and mononuclear cell and mast cell influx in the mMCP-4(-/-) joints. Interestingly, the lower clinical scores in the CII-immunized mMCP-4(-/-) mice coincided with lower serum levels of immunoglobulin G anti-CII antibodies. Our findings identify a pathogenic role of mMCP-4 in autoimmune arthritis.
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| 12. |
- Niemann, Carsten U., et al.
(författare)
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Neutrophil elastase depends on serglycin proteoglycan for localization in granules
- 2007
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 109:10, s. 4478-4486
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Tidskriftsartikel (refereegranskat)abstract
- Granule proteins play a major role in bacterial killing by neutrophils. Serglycin proteoglycan, the major intracellular proteoglycan of hematopoietic cells, has been proposed to play a role in sorting and packing of granule proteins. We examined the content of major neutrophil granule proteins in serglycin knockout mice and found neutrophil elastase absent from mature neutrophils as shown by activity assay, Western blotting, and immunocytochemistry, whereas neutrophil elastase mRNA was present. The localization of other neutrophil granule proteins did not differ between wild-type and serglycin knockout mice. Differential counts and neutrophil ultrastructure were unaffected by the lack of serglycin, indicating that defective localization of neutrophil elastase does not induce neutropenia itself, albeit mutations in the neutrophil elastase gene can cause severe congenital neutropenia or cyclic neutropenia. The virulence of intraperitoneally injected Gram-negative bacteria (Klebsiella pneumoniae)was increased in serglycin knock-out mice compared with wild-type mice, as previously reported for neutrophil elastase knockout mice. Thus, serglycin proteoglycan has an important role in localizing neutrophil elastase in azurophil granules of neutrophils, while localization of other granule proteins must be mediated by other mechanisms.
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| 13. |
- Niemann, Carsten U., et al.
(författare)
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Serglycin proteoglycan is not implicated in localizing exocrine pancreas enzymes to zymogen granules
- 2009
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Ingår i: European Journal of Cell Biology. - : Elsevier BV. - 0171-9335 .- 1618-1298. ; 88:8, s. 473-479
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Tidskriftsartikel (refereegranskat)abstract
- Storage and release of proteins from granules forms the basis of cellular functions as diverse as cell mediated cytotoxicity, neuronal communication, activation of muscle fibres, and release of hormones or digestive enzymes from endocrine and exocrine glands, such as the pancreas. Serglycin is the major intracellular proteoglycan of haematopoietic cells. Serglycin is important for localization of proteins in granules of different haematopoietic cell types. Previous reports have indicated a role for serglycin in granule formation and localization of zymogens in granules of the exocrine pancreas in rat. We here present data showing that serglycin is not present at the protein level in human or murine pancreas. Furthermore, the amount and localization of three exocrine pancreas zymogens (amylase, trypsinogen, and carboxypeptidase A) is not affected by the absence of serglycin in a serglycin knock-out mouse model.
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| 14. |
- Pejler, Gunnar, et al.
(författare)
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Mast cell proteases
- 2007
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Ingår i: Advances in Immunology. - 0065-2776 .- 1557-8445. ; 95, s. 167-255
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells (MCs) are traditionally thought of as a nuisance for its host, for example, by causing many of the symptoms associated with allergic reactions. In addition, recent research has put focus on MCs for displaying harmful effects during various autoimmune disorders. On the other hand, MCs can also be beneficial for its host, for example, by contributing to the defense against insults such as bacteria, parasites, and snake venom toxins. When the MC is challenged by an external stimulus, it may respond by degranulation. In this process, a number of powerful preformed inflammatory “mediators” are released, including cytokines, histamine, serglycin proteoglycans, and several MC-specific proteases: chymases, tryptases, and carboxypeptidase A. Although the exact effector mechanism(s) by which MCs carry out their either beneficial or harmful effects in vivo are in large parts unknown, it is reasonable to assume that these mediators may contribute in profound ways. Among the various MC mediators, the exact biological function of the MC proteases has for a long time been relatively obscure. However, recent progress involving successful genetic targeting of several MC protease genes has generated powerful tools, which will enable us to unravel the role of the MC proteases both in normal physiology as well as in pathological settings. This chapter summarizes the current knowledge of the biology of the MC proteases.
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| 15. |
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| 16. |
- Pejler, Gunnar, et al.
(författare)
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Novel insights into the biological function of mast cell carboxypeptidase A
- 2009
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Ingår i: Trends in immunology. - : Elsevier BV. - 1471-4906 .- 1471-4981. ; 30:8, s. 401-408
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Forskningsöversikt (refereegranskat)abstract
- When mast cells are activated they can respond by releasing their secretory granule compounds, including mast cell-specific proteases of chymase, tryptase and carboxypeptidase A (MC-CPA) type. MC-CPA is a dominant protein component of the mast cell granule and the MC-CPA gene is extremely highly expressed. Despite this, relatively little has been known of its biological function. However, the recent generation of mouse strains lacking MC-CPA has opened up new possibilities for investigations related to this protease. This recent development has revealed a role for MC-CPA in regulating innate immunity responses, including the degradation of harmful substances such as the vasoconstrictive factor endothelin 1 and snake venom toxins. Here, we summarize the current knowledge of MC-CPA.
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| 17. |
- Pejler, Gunnar, et al.
(författare)
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Serglycin proteoglycan : regulating the storage and activities of hematopoietic proteases
- 2009
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Ingår i: Biofactors. - : Wiley. - 0951-6433 .- 1872-8081. ; 35:1, s. 61-68
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Tidskriftsartikel (refereegranskat)abstract
- Serglycin (SG), like all other proteoglycans, consists of a protein "core" to which sulfated and thereby negatively charged polysaccharide chains of glycosaminoglycan type are attached. The recent generation of mice lacking a functional SG gene has revealed a number of biological functions of SG. In particular, it has been shown that SG has a key role in promoting the storage and in regulating the activities of a number of proteases expressed in hematopoietic cell types, most notably various mast cell proteases. In this review, we summarize the recent development in our understanding of the biological function of SG, in particular by focusing on the novel insight provided through analysis of the SG-deficient mouse strain.
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| 18. |
- Piliponsky, Adrian M., et al.
(författare)
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Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis
- 2008
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 14:4, s. 392-398
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell-dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.
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| 19. |
- Presto, Jenny, 1973-
(författare)
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N-Sulfation and Polymerization in Heparan Sulfate Biosynthesis
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Heparan sulfate (HS) is a glycosaminoglycan present in all cell types covalently attached to core proteins forming proteoglycans. HS interacts with different proteins and thereby affects a variety of processes. The biosynthesis of HS takes place in the Golgi network where a complex of the enzymes EXT1 and EXT2 adds N-acetyl glucosamine and glucuronic acid units to the growing chain. The HS chain is N-sulfated by the enzyme N-deacetylase N-sulfotransferase (NDST). N-Sulfation occurs in domains where further modifications (including O-sulfations) take place, giving the chain a complex sulfation pattern.In this thesis, new data about the regulation of NDST enzyme activity is presented. By studying NDST1 with active site mutations overexpressed in HEK 293 cells we show that N-deacetylation is the rate-limiting step in HS N-sulfation and that two different NDST molecules can work on the same GlcN unit.By analyzing recombinant forms of NDST1 and NDST2 we determined the smallest substrate for N-deacetylation to be an octasaccharide. Importantly, the sulfate donor PAPS was shown to regulate the NDST enzymes to modify the HS chain in domains and that binding of PAPS had a stimulating effect on N-deacetylase activity. We could also show that increased levels of NDST1 were obtained when NDST1 was coexpressed with EXT2, while coexpression with EXT1 had the opposite effect. We suggest that EXT2 binds to NDST1, promoting the transport of functional NDST1 to the Golgi network and that EXT1 competes for binding to EXT2. Using cell lines overexpressing EXT proteins, it was demonstrated that overexpression of EXT1 increases HS chain length and coexpression of EXT2 results in even longer chains. The enhancing effect of EXT2 was lost when EXT2 was carrying mutations identical to those found in patients with hereditary multiple exostoses, a syndrome characterized by cartilage-capped bony outgrowths at the long bones..
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| 20. |
- Ringvall, Maria, et al.
(författare)
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Serotonin and histamine storage in mast cell secretory granules is dependent on serglycin proteoglycan
- 2008
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 121:4, s. 1020-1026
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Tidskriftsartikel (refereegranskat)abstract
- Background: Serotonin and histamine are components of human and rodent mast cell secretory granules. Objective: Serotonin and histamine are stored in the same compartment as serglycin proteoglycan. Here we addressed the possibility that serglycin may be involved in their storage and/or release. Methods: The storage and release of histamine and serotonin was studied in bone marrow-derived mast cells (BMMCs) and in peritoneal mast cells from wild-type or serglycin(-/-) mice. Results: Both serotonin and histamine storage in BMMCs was positively correlated with the degree of mast cell differentiation, and the amount of stored amine was reduced in serglycin(-/-) BMMCs compared with wild-type controls. The amounts of histamine/serotonin stored were reflected by the expression levels of histidine decarboxylase and tryptophan hydroxylase 1, respectively. Calcium ionophore activation resulted in serotonin/histamine release both from wild-type and serglycin(-/-) BMMCs. Interestingly, serotonin release was induced in cells lacking intracellular stores of serotonin, suggesting de novo synthesis. The knockout of serglycin affected the levels of stored and released mast cell serotonin and histamine to an even larger extent in in vivo-derived mast cells than in BMMCs. Conclusion: These results establish a previously assumed, but not proven, role of serglycin in storage of histamine and, further, establish for the first time that serotonin storage in mast cells is dependent on serglycin proteoglycan.
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