Ablation of interaction between IL-33 and ST2+ regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration

Author:

Noel Gregory123,Arshad Muhammad Imran123,Filliol Aveline123,Genet Valentine123,Rauch Michel123,Lucas-Clerc Catherine24,Lehuen Agnès5,Girard Jean-Philippe6,Piquet-Pellorce Claire123,Samson Michel123

Affiliation:

1. Institut National de la Santé et de la Recherche Médicale (Inserm), Institut de Recherche Santé Environnement & Travail (IRSET), Rennes, France;

2. Université de Rennes 1, Rennes, France;

3. Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France;

4. Service de Biochimie CHU Rennes, Université de Rennes 1; Rennes, France;

5. Inserm UMRS 1016-CNRS UMR 8104, Institut Cochin, Université Paris, Descartes, France; and

6. Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique (IPBS-CNRS), Université de Toulouse, Toulouse, France

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.

Publisher

American Physiological Society

Subject

Physiology (medical),Gastroenterology,Hepatology,Physiology

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