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Mast Cells as Sentinels: Role of serglycin and mast cell proteases in infection and inflammation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Magnus Åbrink)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells (MCs), normally classified into connective tissue MCs and mucosal MCs, are highly granulated cells found in the interface between the interior and the exterior environment of our body, e.g. skin, airways and gastro-intestinal tract. They react to bacteria, parasites, viruses, and allergens by degranulation and release of premade and newly synthesized inflammatory mediators. The MC-proteases (tryptases, chymases and carboxypeptidase A), histamine and serglycin (SG) proteoglycans are premade mediators. Among these, SG is also expressed in a variety of other immune and non-immune cells. Heparin and chondroitin sulphate glycosaminoglycan chains confer highly negative charge to SG, by which MC-proteases are retained in secretory granules. Deletion of SG cause impaired packing and storage of most MC-proteases. During challenge with Toxoplasma gondii the SG-deficient mice showed significant lower inflammatory cytokine levels in comparison to wild-type mice. Results were consistently similar in vitro, bringing forward the importance of SG in inflammatory cytokine and innate immune responses towards T. gondii. Infection with Trichinella spiralis in SG-/- mice caused increased intestinal enteropathy, a tendency of delayed worm expulsion and increased larval burden in the muscle tissue as compared to wild-type animals. An altered TH2 cytokine response was also observed, and all these effects were not repaired by wild-type MC reconstitution of the SG-/- mice. Altogether, our results suggest that SG is important for tissue homeostasis, and that SG expressing cells seem capable of switching from a SG-dependent storage mode to a SG-independent secretory mode upon infection.

The chymase (MCPT4) expressed by connective tissue MC has been implicated to have a protective role during infection and in limiting inflammation. We explored a protective role by inducing T. gondii infection in the Mcpt4-null mice, and found MCPT4-mediated recruitment of neutrophils and eosinophils via control of cytokine signaling. Endogenous proteins “alarmins” released by dead cells can trigger tissue and cell damage. We conclusively show that chymase efficiently degrades Hsp70 both in vitro and in vivo and that the degradation of other alarmins, e.g. HMGB1, biglycan and IL-33 may also depend on chymase.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 782
Keyword [en]
mast cells, serglycin, chymase, infection, parasite
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-173508ISBN: 978-91-554-8389-0 (print)OAI: oai:DiVA.org:uu-173508DiVA: diva2:523638
Public defence
2012-08-17, C8:305, Uppsala Biomedicine Centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-23 Created: 2012-04-25 Last updated: 2012-08-01Bibliographically approved
List of papers
1. Serglycin contributes to cytokine secretion in Toxoplasma gondii infected mice.
Open this publication in new window or tab >>Serglycin contributes to cytokine secretion in Toxoplasma gondii infected mice.
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(English)Manuscript (preprint) (Other academic)
Keyword
serglycin, infection, mast cells
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-173481 (URN)
Available from: 2012-04-25 Created: 2012-04-25 Last updated: 2012-05-31
2. Chymase mouse mast cell protease 4 regulates inflammatory cytokine levels during Toxoplasma gondii infection
Open this publication in new window or tab >>Chymase mouse mast cell protease 4 regulates inflammatory cytokine levels during Toxoplasma gondii infection
(English)Manuscript (preprint) (Other academic)
Keyword
chymase, mast cell, infection
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-173491 (URN)
Available from: 2012-04-25 Created: 2012-04-25 Last updated: 2012-05-31
3. Serglycin proteoglycans limit enteropathy in Trichinella spiralis-infected mice
Open this publication in new window or tab >>Serglycin proteoglycans limit enteropathy in Trichinella spiralis-infected mice
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2016 (English)In: BMC Immunology, ISSN 1471-2172, E-ISSN 1471-2172, Vol. 17, 15Article in journal (Other academic) Published
Abstract [en]

Background: Serglycin proteoglycans are essential for maturation of secretory granules and for the correct granular storage of cationic proteases in hematopoietic cells, e.g. mast cells. However, little is known about the in vivo functions of serglycin proteoglycans during infection. Here we investigated the potential role of serglycin proteoglycans in host defense after infection with the nematode Trichinella spiralis. Results: Twelve days post infection lack of serglycin proteoglycans caused significantly increased enteropathy. The serglycin-deficient mice showed significantly increased intestinal worm burden, reduced recruitment of mast cells to the intestinal crypts, decreased levels of the mast cell proteases MCPT5 and MCPT6 in intestinal tissue, decreased serum levels of TNF-alpha, IL-1 beta, IL-10 and IL-13, increased levels of IL-4 and total IgE in serum, and increased intestinal levels of the neutrophil markers myeloperoxidase and elastase, as compared to wild type mice. At five weeks post infection, increased larvae burden and inflammation were seen in the muscle tissue of the serglycin-deficient mice. Conclusions: Our results demonstrate that the serglycin-deficient mice were more susceptible to T. spiralis infection and displayed an unbalanced immune response compared to wild type mice. These findings point to an essential regulatory role of serglycin proteoglycans in immunity.

Keyword
Mast cell; Parasite; Serglycin; Infection; Trichinella spiralis; Intestine
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-173492 (URN)10.1186/s12865-016-0155-y (DOI)000379305000001 ()27267469 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council FormasSwedish Cancer SocietyGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
Available from: 2012-04-25 Created: 2012-04-25 Last updated: 2017-12-07Bibliographically approved
4. Mast cell chymase can limit danger-induced inflammation by degradation of heat shock protein 70,biglycan,HMGB1 and IL-33
Open this publication in new window or tab >>Mast cell chymase can limit danger-induced inflammation by degradation of heat shock protein 70,biglycan,HMGB1 and IL-33
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-173495 (URN)
Available from: 2012-04-25 Created: 2012-04-25 Last updated: 2012-05-31

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