The IL-33/amphiregulin axis mediates immunoregulation in acute and chronic liver disease

Background In autoimmune liver diseases, the alarmin IL-33 is released from necrotic hepatocytes. IL-33 binds to the ST2 receptor thereby activating group 2 innate lymphoid cells (ILC2) and regulatory T cells (Tregs). Both cell types express amphiregulin (AREG), which has been associated with tissue repair, immunosuppression, fibrogenesis, and liver carcinogenesis. Here we investigated the immunosuppressive role of AREG in acute and chronic liver inflammation.

Methods Acute immune-mediated hepatitis was induced by ConA administration to WT or Areg-/- mice. To study IL-33-mediated immunosuppression mice received IL-33 three days before ConA challenge. 12 weeks old Mdr2-/- mice were used as a model for chronic liver inflammation resembling PSC.

Results Hepatic expression of Il33 and Areg was elevated in acute and chronic hepatitis, in which Areg was the most up-regulated EGFR ligand. ILC2 and ST2+ Tregs showed increased expression of AREG in acute hepatitis, whereas Tregs expressed less AREG in chronic liver inflammation. IL-33 pre-treatment resulted in strong AREG expression by ILC2 and ST2+ Tregs and prevented acute hepatitis. Interestingly, IL-33-induced ST2+ Tregs exhibited an immunosuppressive phenotype. Areg-/- mice were more sensitive towards ConA hepatitis, which corresponded to stronger activation of ILC2 and a reduced frequency of ST2+ Tregs in the liver.

Conclusion In acute hepatitis, IL-33 seems to mediate immunoregulation by expansion and activation of AREG-expressing ILC2 and ST2+ Tregs. In chronic liver disease, immunosuppressive function of Tregs might be attenuated because of reduced AREG expression, critically involved in maintenance of Treg function particularly under inflammatory condition.

Publication History

Article published online:
26 January 2022