Published ahead of print on October 20, 2009 Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2008-0426OC
Submitted on November 4, 2008 MMP-19 Deficiency Promotes Tenascin-C Accumulation and Allergen-induced Airway Inflammation.Maud M Gueders1,1 Laboratory of Biology of Tumours and Development, GIGA-research (GIGA-Ił and GIGA-cancer), University of Liege and Centre Hospitalier Universitaire (CHU-Liege), Liege, Belgium; Department of Respiratory Diseases, GIGA-research (GIGA-Ił and GIGA-cancer), University of Liege and Centre Hospitalier Universitaire (CHU-Liege), Liege, Belgium, 2 Physiology, Monash Univeristy, Melbourne, Victoria, Australia, 3 Laboratory of Biology of Tumours and Development, GIGA-research (GIGA-Ił and GIGA-cancer), University of Liege and Centre Hospitalier Universitaire (CHU-Liege), Liege, Belgium, 4 Unité INSERM U774, Institut Pasteur de Lille, Lille, France, 5 Department of Respiratory Diseases, GIGA-research (GIGA-Ił and GIGA-cancer), University of Liege and Centre Hospitalier Universitaire (CHU-Liege), Liege, Belgium, 6 Laboratory of Biology and Tumors Development, GIGA-research (GIGA-Ił and GIGA-cancer), University of Liege and Centre Hospitalier Universitaire (CHU-Liege), Liege, Belgium, 7 Departamento de Bioquimica y Biologia Molecular, Universidad de Oviedo, Instituto Universitario de Oncologia, Oviedo , Spain, 8 Laboratory of Biology and Tumors Development, GIGA-research (GIGA-Ił and GIGA-cancer), University of Liege and Centre Hospitalier Universitaire (CHU-Liege), Liege, Belgium; Department of Respiratory Diseases, GIGA-research (GIGA-Ił and GIGA-cancer), University of Liege and Centre Hospitalier Universitaire (CHU-Liege), Liege, Belgium * To whom correspondence should be addressed. E-mail: didier.cataldo{at}ulg.ac.be.
Matrix metalloproteinases (MMPs) recently appeared as key regulators of inflammation, allowing recruitment and clearance of inflammatory cells and modifying the biological activity of many peptidic mediators by cleavage. MMP-19 is a newly described MMP and preferentially cleaves matrix proteins such as collagens and tenascin-C. The role of MMP-19 in asthma has not been described to date. The purpose of the present study was to assess MMP-19 expression in a murine asthma model and to address biological effects of MMP-19 deficiency in mice. Allergen-exposed wild-type (WT) mice displayed an increased expression of MMP-19 mRNA and an increased number of MMP-19-positive cells in the lungs detected by immunohistochemistry. After allergen challenge of MMP-19 knockout (MMP-19-/-) mice, an exacerbated eosinophilic inflammation was detected in bronchoalveolar lavage fluid and bronchial tissue along with an increased airway responsiveness to methacholine. A shift towards increased Th2-driven inflammation in MMP-19-/- mice was demonstrated by 1) increased numbers of cells expressing the IL-33 receptor T1/ST2 in lung parenchyma, 2) increased IgG1 levels in serum and 3) higher levels of IL-13 and CCL11 in lung extracts. Tenascin-C was found accumulated in peribronchial areas of MMP-19-/- after allergen challenges as assessed by Western blot and immunohistochemistry analysis. We conclude that MMP-19 is a new mediator in asthma, preventing tenascin-C accumulation and directly or indirectly controlling Th2-driven airway eosinophilia and airway hyperreactivity . Our data suggest that MMP-19 might act on Th2 inflammation homeostasis through preventing tenascin protein accumulation. Key words: eosinophils • inflammation • lung • MMP-19 • knockout mice
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