title: Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells.
abstract: Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33(95-270), IL-33(107-270), and IL-33(109-270), were 30-fold more potent than full-length human IL-33(1-270) for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; and.
authors.forename: Emma
authors.initials: E
authors.lastname: Lefrançais
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; and.
authors.forename: Anais
authors.initials: A
authors.lastname: Duval
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; and.
authors.forename: Emilie
authors.initials: E
authors.lastname: Mirey
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; and.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Roga
authors.affiliation: INSERM UMR 1043, CNRS UMR 5282, Centre de Physiopathologie de Toulouse-Purpan, Université de Toulouse, F-31024 Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Espinosa
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; and jean-philippe.girard@ipbs.fr corinne.cayrol@ipbs.fr.
authors.forename: Corinne
authors.initials: C
authors.lastname: Cayrol
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; and jean-philippe.girard@ipbs.fr corinne.cayrol@ipbs.fr.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D000067596:Interleukin-33; D007378:Interleukins / Q000737:chemistry* / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology*; D008407:Mast Cells / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010447:Peptide Hydrolases / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C506536:IL33 protein, human; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D010447:Peptide Hydrolases
keywords: IL-33; allergic inflammation; cytokine; innate lymphoid cells; mast cell protease