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Abstract：
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 in vitro. 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 vitro. In addition, Tregs from Areg-/- mice were impaired in their capacity to suppress CD4+ T-cell activation in vitro. 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.
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 in vitro. 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 vitro. In addition, Tregs from Areg-/- mice were impaired in their capacity to suppress CD4+ T-cell activation in vitro. 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.
摘要：
■警报蛋白IL-33与免疫介导的肝脏疾病的病理学有关。IL-33激活表达IL-33受体ST2的调节性T细胞(Tregs)和2型先天淋巴样细胞(ILC2s)。我们先前已经表明，内源性IL-33/ST2信号激活ILC2s，从而加重小鼠免疫介导的肝炎中的肝损伤。然而,在诱导肝炎之前用外源性IL-33治疗小鼠改善了疾病的严重程度。由于IL-33诱导对Treg功能至关重要的双调蛋白（AREG）的表达，我们研究了ST2+Treg/AREG轴在免疫介导性肝炎中的免疫调节作用.
■C57BL/6，ST2缺陷（Il1rl1-/-）和Areg-/-小鼠接受伴刀豆球蛋白A诱导免疫介导的肝炎。在诱导免疫介导的肝炎之前,用IL-33预处理Foxp3Cre+xST2fl/fl小鼠。通过过继转移实验和抑制测定评估Treg功能。体外研究了AREG和IL-33对ST2Tregs和ILC2s的影响。通过流式细胞术分析免疫细胞表型。
■我们将IL-33反应性ST2+Tregs鉴定为小鼠肝脏中的效应Treg亚群，在免疫介导的肝炎中高度激活。Il1rl1-/-小鼠中内源性IL-33信号的缺乏加重了疾病病理。这与Treg活化降低有关。在诱导肝炎之前，外源性IL-33激活的ST2Treg的过继转移抑制了炎性T细胞反应并改善了疾病病理。我们进一步显示，在免疫介导的肝炎中，肝ST2Tregs和ILC2s表达增加。Areg-/-小鼠出现更严重的肝损伤，这与炎症肝脏中ILC2激活增强和ST2+Tregs减少有关。外源性AREG在体外抑制ILC2细胞因子表达并增强ST2+Treg活化。此外,来自Areg-/-小鼠的Treg在体外抑制CD4+T细胞活化的能力受损。此外，在疾病诱导前应用外源性IL-33不能保护缺乏ST2+Tregs的Foxp3Cre+xST2fl/fl小鼠免受免疫介导的肝炎。总之,我们描述了ST2+Treg/AREG轴在免疫介导的肝炎的免疫调节作用，其中AREG抑制肝脏ILC2s的激活，同时维持ST2+Tregs并增强其在肝脏炎症中的免疫抑制能力。
■C57BL/6，ST2缺陷（Il1rl1-/-）和Areg-/-小鼠接受伴刀豆球蛋白A诱导免疫介导的肝炎。在诱导免疫介导的肝炎之前,用IL-33预处理Foxp3Cre+xST2fl/fl小鼠。通过过继转移实验和抑制测定评估Treg功能。体外研究了AREG和IL-33对ST2Tregs和ILC2s的影响。通过流式细胞术分析免疫细胞表型。
■我们将IL-33反应性ST2+Tregs鉴定为小鼠肝脏中的效应Treg亚群，在免疫介导的肝炎中高度激活。Il1rl1-/-小鼠中内源性IL-33信号的缺乏加重了疾病病理。这与Treg活化降低有关。在诱导肝炎之前，外源性IL-33激活的ST2Treg的过继转移抑制了炎性T细胞反应并改善了疾病病理。我们进一步显示，在免疫介导的肝炎中，肝ST2Tregs和ILC2s表达增加。Areg-/-小鼠出现更严重的肝损伤，这与炎症肝脏中ILC2激活增强和ST2+Tregs减少有关。外源性AREG在体外抑制ILC2细胞因子表达并增强ST2+Treg活化。此外,来自Areg-/-小鼠的Treg在体外抑制CD4+T细胞活化的能力受损。此外，在疾病诱导前应用外源性IL-33不能保护缺乏ST2+Tregs的Foxp3Cre+xST2fl/fl小鼠免受免疫介导的肝炎。总之,我们描述了ST2+Treg/AREG轴在免疫介导的肝炎的免疫调节作用，其中AREG抑制肝脏ILC2s的激活，同时维持ST2+Tregs并增强其在肝脏炎症中的免疫抑制能力。
