title: Ablation of interaction between IL-33 and ST2+ regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration.
abstract: The IL-33/ST2 axis plays a protective role in T-cell-mediated hepatitis, but little is known about the functional impact of endogenous IL-33 on liver immunopathology. We used IL-33-deficient mice to investigate the functional effect of endogenous IL-33 in concanavalin A (Con A)-hepatitis. IL-33(-/-) mice displayed more severe Con A liver injury than wild-type (WT) mice, consistent with a hepatoprotective effect of IL-33. The more severe hepatic injury in IL-33(-/-) mice was associated with significantly higher levels of TNF-α and IL-1β and a larger number of NK cells infiltrating the liver. The expression of Th2 cytokines (IL-4, IL-10) and IL-17 was not significantly varied between WT and IL-33(-/-) mice following Con A-hepatitis. The percentage of CD25(+) NK cells was significantly higher in the livers of IL-33(-/-) mice than in WT mice in association with upregulated expression of CXCR3 in the liver. Regulatory T cells (Treg cells) strongly infiltrated the liver in both WT and IL-33(-/-) mice, but Con A treatment increased their membrane expression of ST2 and CD25 only in WT mice. In vitro, IL-33 had a significant survival effect, increasing the total number of splenocytes, including B cells, CD4(+) and CD8(+) T cells, and the frequency of ST2(+) Treg cells. In conclusion, IL-33 acts as a potent immune modulator protecting the liver through activation of ST2(+) Treg cells and control of NK cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;
authors.forename: Gregory
authors.initials: G
authors.lastname: Noel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Arshad
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;
authors.forename: Aveline
authors.initials: A
authors.lastname: Filliol
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;
authors.forename: Valentine
authors.initials: V
authors.lastname: Genet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Rauch
authors.affiliation: Université de Rennes 1, Rennes, France; Service de Biochimie CHU Rennes, Université de Rennes 1; Rennes, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Lucas-Clerc
authors.affiliation: Inserm UMRS 1016-CNRS UMR 8104, Institut Cochin, Université Paris, Descartes, France; and.
authors.forename: Agnès
authors.initials: A
authors.lastname: Lehuen
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique (IPBS-CNRS), Université de Toulouse, Toulouse, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;
authors.forename: Claire
authors.initials: C
authors.lastname: Piquet-Pellorce
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France; Université de Rennes 1, Rennes, France; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France; michel.samson@univ-rennes1.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002634:Chemotaxis, Leukocyte; D003208:Concanavalin A; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006505:Hepatitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000276:immunology* / Q000378:metabolism; D000067596:Interleukin-33 / Q000172:deficiency* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000294:innervation* / Q000378:metabolism; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D018836:Inflammation Mediators; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D003208:Concanavalin A
keywords: ST2 receptor; concanavalin A-hepatitis; immune cells; interleukin-33-deficient mice; liver; regulatory T cells