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

Gregory Noel (1) , Muhammad Imran Arshad (1) , Aveline Filliol (1) , Valentine Genet (1) , Michel Rauch (1) , Catherine Lucas-Clerc (2) , Agnes Lehuen (3) , Jean-Philippe Girard (4) , Claire Piquet-Pellorce (1) , Michel Samson (1)

1 Irset - Institut de recherche en santé, environnement et travail
2 Laboratoire de biochimie générale
3 IC UM3 (UMR 8104 / U1016) - Institut Cochin
4 IPBS - Institut de pharmacologie et de biologie structurale

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-alpha and IL-1 beta 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.

Mots clés: expression; alarmin; cytokine il-33; responses; tolerance; mice; accumulation; hepatocytes; disease; signals

Domaines: Hépatologie et Gastroentérologie; Immunologie

Gregory Noel, Muhammad Imran Arshad, Aveline Filliol, Valentine Genet, Michel Rauch, et al.. Ablation of interaction between IL-33 and ST2(+) regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration. AJP - Gastrointestinal and Liver Physiology, 2016, 311 (2), pp.G313--G323. ⟨10.1152/ajpgi.00097.2016⟩. ⟨hal-01366372⟩