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

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2016-08, Vol.311 (2), p.G313-G323
• Main Authors: Noel, Gregory, Arshad, Muhammad Imran, Filliol, Aveline, Genet, Valentine, Rauch, Michel, Lucas-Clerc, Catherine, Lehuen, Agnès, Girard, Jean-Philippe, Piquet-Pellorce, Claire, Samson, Michel
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Chemical and Drug Induced Liver Injury - prevention & control; Chemotaxis, Leukocyte; Concanavalin A; Cytokines - immunology; Cytokines - metabolism; Disease Models, Animal; Genetic Predisposition to Disease; Hepatitis - immunology; Hepatitis - metabolism; Hepatitis - pathology; Hepatitis - prevention & control; Human health and pathology; Hépatology and Gastroenterology; Immunology; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Interleukin-1 Receptor-Like 1 Protein - immunology; Interleukin-1 Receptor-Like 1 Protein - metabolism; Interleukin-33 - deficiency; Interleukin-33 - genetics; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Life Sciences; Liver - innervation; Liver - metabolism; Lymphocyte Activation; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Signal Transduction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00097.2016

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.