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IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice
BACKGROUND: 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. OBJECTIVES: We aimed to determine the effects and mechanism of IL-33 on the de...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mosby
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258609/ https://www.ncbi.nlm.nih.gov/pubmed/24985397 http://dx.doi.org/10.1016/j.jaci.2014.05.011 |
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author | Li, Dong Guabiraba, Rodrigo Besnard, Anne-Gaëlle Komai-Koma, Mousa Jabir, Majid S. Zhang, Li Graham, Gerard J. Kurowska-Stolarska, Mariola Liew, Foo Y. McSharry, Charles Xu, Damo |
author_facet | Li, Dong Guabiraba, Rodrigo Besnard, Anne-Gaëlle Komai-Koma, Mousa Jabir, Majid S. Zhang, Li Graham, Gerard J. Kurowska-Stolarska, Mariola Liew, Foo Y. McSharry, Charles Xu, Damo |
author_sort | Li, Dong |
collection | PubMed |
description | BACKGROUND: 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. OBJECTIVES: We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. |
format | Online Article Text |
id | pubmed-4258609 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Mosby |
record_format | MEDLINE/PubMed |
spelling | pubmed-42586092014-12-09 IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice Li, Dong Guabiraba, Rodrigo Besnard, Anne-Gaëlle Komai-Koma, Mousa Jabir, Majid S. Zhang, Li Graham, Gerard J. Kurowska-Stolarska, Mariola Liew, Foo Y. McSharry, Charles Xu, Damo J Allergy Clin Immunol Mechanisms of Allergy and Clinical Immunology BACKGROUND: 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. OBJECTIVES: We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Mosby 2014-12 /pmc/articles/PMC4258609/ /pubmed/24985397 http://dx.doi.org/10.1016/j.jaci.2014.05.011 Text en © 2014 The Authors https://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). |
spellingShingle | Mechanisms of Allergy and Clinical Immunology Li, Dong Guabiraba, Rodrigo Besnard, Anne-Gaëlle Komai-Koma, Mousa Jabir, Majid S. Zhang, Li Graham, Gerard J. Kurowska-Stolarska, Mariola Liew, Foo Y. McSharry, Charles Xu, Damo IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice |
title | IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice |
title_full | IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice |
title_fullStr | IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice |
title_full_unstemmed | IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice |
title_short | IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice |
title_sort | il-33 promotes st2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice |
topic | Mechanisms of Allergy and Clinical Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258609/ https://www.ncbi.nlm.nih.gov/pubmed/24985397 http://dx.doi.org/10.1016/j.jaci.2014.05.011 |
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