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The role of mast cell proteases in allergic disease and apoptosis

Waern, Ida (2012). The role of mast cell proteases in allergic disease and apoptosis. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2012:50
ISBN 978-91-576-7697-9
[Doctoral thesis]

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Abstract

Mast cells (MCs) are key effector cells in allergic reactions, through the release of a wide variety of granule-stored and de novo synthesized inflammatory mediators. The MC secretory granules contain exceedingly high levels of serglycin proteoglycan and the heparin-binding proteases chymase, tryptase and carboxypeptidase A.

In this thesis the contribution of mouse mast cell protease (mMCP)-4, which is thought to be the functional homolog to the human chymase, was studied in the context of allergic airway inflammation. Using two models of allergic airway inflammation, wild-type (WT) and mMCP-4 deficient (mMCP-4-/-) mice were treated with ovalbumin (OVA) or with house dust mite (HDM) extract. We found that the OVA challenged mMCP-4-/- mice displayed increased airway hyperreactivity and lung eosinophilia and in the HDM model they displayed increased serum IgE levels. Moreover, the level of IL-33, a pro-inflammatory cytokine, was enhanced in the lung tissue in mMCP-4-/- mice compared to WT mice after HDM-treatment.

The active proteases stored in MC granules have the ability to cleave a number of components upon degranulation. We could demonstrate that proteolytic degradation of IL-13 by MCs is mediated by a serine protease, dependent on serglycin proteoglycan for its storage.

Permeabilization of lysosomal membranes often leads to apoptosis and the released proteases take part in this process, activating pro-apoptotic compounds. We have found that serglycin-/- MCs are more resistant to apoptosis induced by secretory granule damage. We showed that serglycin-/- MCs exhibited reduced caspase-3 activity and protease activity in the cytosol compared to WT cells.

Taken together, the studies in this thesis suggest that MCs chymase plays a protective role in the development of allergic airway inflammation and this could possibly be explained by chymases ability to degrade the pro-inflammatory cytokine, IL-33. In addition, we also suggest that serglycin proteoglycan and serglycin-dependent MC proteases participate in IL-13 degradation as well as in MC apoptosis induced by secretory granule damage.

Authors/Creators:Waern, Ida
Title:The role of mast cell proteases in allergic disease and apoptosis
Series/Journal:Acta Universitatis agriculturae Sueciae (1652-6880)
Year of publishing :2012
Volume:2012:50
Number of Pages:66
Papers/manuscripts:
NumberReferences
I.Waern I., Jonasson S., Hjoberg J., Bucht A., Åbrink M., Pejler G. and Wernersson S. (2009). Mouse mast cell protease 4 is the major chymase in murine airways and has a protective role in allergic airway inflammation. Journal of Immunology. 183(10):6369-76.
II.Waern I., Lundequist A., Pejler G. and Wernersson S. (2012). Mast cell chymase modulates IL-33 levels and controls allergic sensitization in dustmite induced airway inflammation. Manuscript.
III.Waern I., Karlsson I., Thorpe M., Schlenner S. M., Feyerabend T. B., Rodewald H-R., Åbrink M., Hellman L., Pejler G. and Wernersson S. (2012). Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis. Biological Chemistry ISSN (online) 1437-4315. DOI: 10.1515/bc-2012-0189.
IV.Melo F. R., Waern I., Rönnberg E., Åbrink M., Lee D. M., Schlenner S. M., Feyerabend T. B., Rodewald H-R., Turk B., Wernersson S. and Pejler G. (2011). A role for sergycin proteoglycan in mast cell apoptosis induced by a secretory granule-mediated pathway. Journal of Biological Chemistry. 286(7):5423-33.
Place of Publication:Uppsala
Publisher:Dept. of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences
ISBN for printed version:978-91-576-7697-9
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X30 Life sciences
Subjects:(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Biochemistry and Molecular Biology
(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Cell Biology
(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Immunology (Immunology in the medical area to be 30110)
(A) Swedish standard research categories 2011 > 4 Agricultural Sciences > 403 Veterinary Science > Medical Bioscience
Agrovoc terms:mast cells, proteases, proteoglycans, human diseases, asthma, hypersensitivity, apoptosis
Keywords:mast cells, serglycin proteoglycan, protease, chymase, allergic airway inflammation, asthma, apoptosis
URN:NBN:urn:nbn:se:slu:epsilon-e-607
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-607
ID Code:9026
Department:(VH) > Dept. of Anatomy, Physiology and Biochemistry
Deposited By: Ida Waern
Deposited On:06 Sep 2012 13:21
Metadata Last Modified:02 Dec 2014 10:51

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