title: IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom; INRA, Infectiologie et Santé Publique, Nouzilly, France.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Guabiraba
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Anne-Gaëlle
authors.initials: AG
authors.lastname: Besnard
authors.affiliation: Department of Haematology & Immunology, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.
authors.forename: Mousa
authors.initials: M
authors.lastname: Komai-Koma
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom; Department of Biotechnology, University of Technology, Baghdad, Iraq.
authors.forename: Majid S
authors.initials: MS
authors.lastname: Jabir
authors.affiliation: Institute of Laboratory Animal Science, Peking Union Medical College, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Graham
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Mariola
authors.initials: M
authors.lastname: Kurowska-Stolarska
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom; CEGMR, King Abdul-Aziz University, Jeddah, Saudi Arabia.
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom. Electronic address: Charles.McSharry@glasgow.ac.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: McSharry
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom; Institute of Laboratory Animal Science, Peking Union Medical College, Beijing, China. Electronic address: Damo.Xu@glasgow.ac.uk.
authors.forename: Damo
authors.initials: D
authors.lastname: Xu
mesh_terms: D000818:Animals; D005355:Fibrosis; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D053773:Transforming Growth Factor beta1
keywords: IL-33; alternatively activated macrophages; lung fibrosis; type 2 innate lymphoid cells