title: A Proinflammatory Role of Type 2 Innate Lymphoid Cells in Murine Immune-Mediated Hepatitis.
abstract: Type 2 innate lymphoid cells (ILC2) mediate inflammatory immune responses in the context of diseases triggered by the alarmin IL-33. In recent years, IL-33 has been implicated in the pathogenesis of immune-mediated liver diseases. However, the immunoregulatory function of ILC2s in the inflamed liver remains elusive. Using the murine model of Con A-induced immune-mediated hepatitis, we showed that selective expansion of ILC2s in the liver was associated with highly elevated hepatic IL-33 expression, severe liver inflammation, and infiltration of eosinophils. CD4+T cell-mediated tissue damage and subsequent IL-33 release were responsible for the activation of hepatic ILC2s that produced the type 2 cytokines IL-5 and IL-13 during liver inflammation. Interestingly, ILC2 depletion correlated with less severe hepatitis and reduced accumulation of eosinophils in the liver, whereas adoptive transfer of hepatic ILC2s aggravated liver inflammation and tissue damage. We further showed that, despite expansion of hepatic ILC2s, 3-d IL-33 treatment before Con A challenge potently suppressed development of immune-mediated hepatitis. We found that IL-33 not only activated hepatic ILC2s but also expanded CD4+Foxp3+regulatory T cells (Treg) expressing the IL-33 receptor ST2 in the liver. This Treg subset also accumulated in the liver during resolution of immune-mediated hepatitis. In summary, hepatic ILC2s are poised to respond to the release of IL-33 upon liver tissue damage through expression of type 2 cytokines thereby participating in the pathogenesis of immune-mediated hepatitis. Inflammatory activity of ILC2s might be regulated by IL-33-elicited ST2+Tregs that also arise in immune-mediated hepatitis.
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Katrin
authors.initials: K
authors.lastname: Neumann
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Khalil
authors.initials: K
authors.lastname: Karimi
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Jana
authors.initials: J
authors.lastname: Meiners
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Ruth
authors.identifier: 0000-0002-4074-6064
authors.initials: R
authors.lastname: Voetlause
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Silja
authors.identifier: 0000-0001-9177-1414
authors.initials: S
authors.lastname: Steinmann
authors.affiliation: 1. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany.
authors.forename: Werner
authors.identifier: 0000-0001-6847-3769
authors.initials: W
authors.lastname: Dammermann
authors.affiliation: 1. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lüth
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Farahnaz
authors.identifier: 0000-0003-3847-5514
authors.initials: F
authors.lastname: Asghari
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Claudia
authors.identifier: 0000-0001-9905-6386
authors.initials: C
authors.lastname: Wegscheid
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Horst
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany; and g.tiegs@uke.de.
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D016207:Cytokines; D000067596:Interleukin-33