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Serglycin proteoglycans limit enteropathy in Trichinella spiralis-infected mice
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
Swedish University of Agricultural Sciences.
Uppsala universitet.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
Visa övriga samt affilieringar
2016 (Engelska)Ingår i: BMC Immunology, ISSN 1471-2172, E-ISSN 1471-2172, Vol. 17, artikel-id 15Artikel i tidskrift (Övrigt vetenskapligt) 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.

Ort, förlag, år, upplaga, sidor
2016. Vol. 17, artikel-id 15
Nyckelord [en]
Mast cell; Parasite; Serglycin; Infection; Trichinella spiralis; Intestine
Nationell ämneskategori
Immunologi inom det medicinska området
Forskningsämne
Immunologi
Identifikatorer
URN: urn:nbn:se:uu:diva-173492DOI: 10.1186/s12865-016-0155-yISI: 000379305000001PubMedID: 27267469OAI: oai:DiVA.org:uu-173492DiVA, id: diva2:523545
Forskningsfinansiär
VetenskapsrådetForskningsrådet FormasCancerfondenGöran Gustafssons Stiftelse för främjande av vetenskaplig forskning vid Uppsala universitet och Kungl tekniska högskolan (UU/KTH)Tillgänglig från: 2012-04-25 Skapad: 2012-04-25 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
Ingår i avhandling
1. Mast Cells as Sentinels: Role of serglycin and mast cell proteases in infection and inflammation
Öppna denna publikation i ny flik eller fönster >>Mast Cells as Sentinels: Role of serglycin and mast cell proteases in infection and inflammation
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2012. s. 67
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 782
Nyckelord
mast cells, serglycin, chymase, infection, parasite
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Immunologi
Identifikatorer
urn:nbn:se:uu:diva-173508 (URN)978-91-554-8389-0 (ISBN)
Disputation
2012-08-17, C8:305, Uppsala Biomedicine Centrum, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2012-05-23 Skapad: 2012-04-25 Senast uppdaterad: 2012-08-01Bibliografiskt granskad

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Roy, AnanyaDagälv, AndersKjellén, Lena
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NeuroonkologiUppsala universitetInstitutionen för medicinsk biokemi och mikrobiologi
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