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Doctoral thesis, 2012

The role of mast cell proteases in allergic disease and apoptosis

Waern, Ida

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.

Keywords

mast cells; serglycin proteoglycan; protease; chymase; allergic airway inflammation; asthma; apoptosis

Published in

Acta Universitatis Agriculturae Sueciae
2012, number: 2012:50
ISBN: 978-91-576-7697-9
Publisher: Dept. of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences

    UKÄ Subject classification

    Medical Bioscience
    Immunology

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/79070