IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice

Li, D. et al. (2014) IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. Journal of Allergy and Clinical Immunology, 134(6), 1422-1432.e11. (doi: 10.1016/j.jaci.2014.05.011) (PMID:24985397) (PMCID:PMC4258609)

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Background<p></p> The initiation and regulation of pulmonary fibrosis are not well understood. IL-33, an important cytokine for respiratory diseases, is overexpressed in the lungs of patients with idiopathic pulmonary fibrosis.<p></p> Objectives<p></p> We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis.<p></p> Methods<p></p> Lung fibrosis was induced by bleomycin in wild-type or Il33r (St2)−/− C57BL/6 mice treated with the recombinant mature form of IL-33 or anti–IL-33 antibody or transferred with type 2 innate lymphoid cells (ILC2s). The development and severity of fibrosis was evaluated based on lung histology, collagen levels, and lavage cytology. Cytokine and chemokine levels were quantified by using quantitative PCR, ELISA, and cytometry.<p></p> Results<p></p> IL-33 is constitutively expressed in lung epithelial cells but is induced in macrophages by bleomycin. Bleomycin enhanced the production of the mature but reduced full-length form of IL-33 in lung tissue. ST2 deficiency, anti–IL-33 antibody treatment, or alveolar macrophage depletion attenuated and exogenous IL-33 or adoptive transfer of ILC2s enhanced bleomycin-induced lung inflammation and fibrosis. These pathologic changes were accompanied, respectively, by reduced or increased IL-33, IL-13, TGF-β1, and inflammatory chemokine production in the lung. Furthermore, IL-33 polarized M2 macrophages to produce IL-13 and TGF-β1 and induced the expansion of ILC2s to produce IL-13 in vitro and in vivo.<p></p> Conclusions<p></p> IL-33 is a novel profibrogenic cytokine that signals through ST2 to promote the initiation and progression of pulmonary fibrosis by recruiting and directing inflammatory cell function and enhancing profibrogenic cytokine production in an ST2- and macrophage-dependent manner.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Liew, Prof Foo and Xu, Dr Damo and Besnard, Dr Anne-Gaelle and Komai-Koma, Dr Mousa and Kurowska-Stolarska, Professor Mariola and Guabiraba Brito, Dr Rodrigo and McSharry, Dr Charles and Graham, Professor Gerard
Authors: Li, D., Guabiraba Brito, R., Besnard, A.-G., Komai-Koma, M., Jabir, M. S., Zhang, L., Graham, G. J., Kurowska-Stolarska, M., Liew, F. Y., McSharry, C., and Xu, D.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Allergy and Clinical Immunology
ISSN (Online):1097-6825
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Journal of Allergy and Clinical Immunology 134(6):1422-1432.e11
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
514991IL-33: a novel cytokine that integrates innate and adaptive immune activation in inflammatory arthritisDamo XuArthritis Research UK (ARC)18912III -IMMUNOLOGY