The ST2 + Treg/amphiregulin axis protects from immune-mediated hepatitis

• Published in: Frontiers in immunology 2024-03, Vol.15, p.1351405-1351405
• Main Authors: Wachtendorf, Selina, Jonin, Fitriasari, Ochel, Aaron, Heinrich, Fabian, Westendorf, Astrid M, Tiegs, Gisa, Neumann, Katrin
• Format: Article
• Language: English
• Subjects: amphiregulin; Amphiregulin - metabolism; Animals; hepatic immunoregulation; Hepatitis; ILC2s; Immunity, Innate; Immunology; Interleukin-1 Receptor-Like 1 Protein - metabolism; Interleukin-33; liver inflammation; Lymphocytes; Mice; Mice, Inbred C57BL; ST2+ Tregs; T-Lymphocytes, Regulatory; Treg maintenance and function
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1351405

The alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2 Treg/AREG axis in immune-mediated hepatitis. C57BL/6, ST2-deficient (Il1rl1 ) and Areg mice received concanavalin A to induce immune-mediated hepatitis. Foxp3Cre x ST2fl/fl mice were pre-treated with IL-33 before induction of immune-mediated hepatitis. Treg function was assessed by adoptive transfer experiments and suppression assays. The effects of AREG and IL-33 on ST2 Tregs and ILC2s were investigated . Immune cell phenotype was analyzed by flow cytometry. We identified IL-33-responsive ST2 Tregs as an effector Treg subset in the murine liver, which was highly activated in immune-mediated hepatitis. Lack of endogenous IL-33 signaling in Il1rl1 mice aggravated disease pathology. This was associated with reduced Treg activation. Adoptive transfer of exogenous IL-33-activated ST2 Tregs before induction of hepatitis suppressed inflammatory T-cell responses and ameliorated disease pathology. We further showed increased expression of AREG by hepatic ST2 Tregs and ILC2s in immune-mediated hepatitis. Areg mice developed more severe liver injury, which was associated with enhanced ILC2 activation and less ST2 Tregs in the inflamed liver. Exogenous AREG suppressed ILC2 cytokine expression and enhanced ST2 Treg activation . In addition, Tregs from Areg mice were impaired in their capacity to suppress CD4 T-cell activation . Moreover, application of exogenous IL-33 before disease induction did not protect Foxp3Cre x ST2fl/fl mice lacking ST2 Tregs from immune-mediated hepatitis. In summary, we describe an immunoregulatory role of the ST2 Treg/AREG axis in immune-mediated hepatitis, in which AREG suppresses the activation of hepatic ILC2s while maintaining ST2 Tregs and reinforcing their immunosuppressive capacity in liver inflammation.