Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Front Immunol. 2024 Mar 20;15:1351405. doi: 10.3389/fimmu.2024.1351405. eCollection 2024.
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.
警报素 IL-33 已被牵连到免疫介导的肝脏疾病的病理中。IL-33 激活表达 IL-33 受体 ST2 的调节性 T 细胞（Treg）和 2 型先天淋巴样细胞（ILC2）。我们之前已经表明，内源性 IL-33/ST2 信号激活 ILC2，加剧了小鼠免疫介导的肝炎中的肝损伤。然而，在肝炎诱导之前用外源性 IL-33 治疗小鼠可改善疾病严重程度。由于 IL-33 诱导调节性 T 细胞功能所必需的 Amphiregulin（AREG）的表达，我们研究了 ST2 Treg/AREG 轴在免疫介导的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 以诱导免疫介导的肝炎。Foxp3Cre x ST2fl/fl 小鼠在诱导免疫介导的肝炎前用 IL-33 预处理。通过过继转移实验和抑制实验评估 Treg 功能。研究了 AREG 和 IL-33 对 ST2 Treg 和 ILC2 的影响。通过流式细胞术分析免疫细胞表型。
我们确定了 IL-33 反应性 ST2 Treg 作为小鼠肝脏中效应性 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 信号的缺失加重了疾病病理学。这与 Treg 激活减少有关。在肝炎诱导之前过继转移外源性 IL-33 激活的 ST2 Treg 可抑制炎症性 T 细胞反应并改善疾病病理学。我们进一步表明，在免疫介导的肝炎中，肝 ST2 Treg 和 ILC2 表达增加的 AREG。Areg 小鼠发生更严重的肝损伤，与 ILC2 激活增强和炎症肝中 ST2 Treg 减少有关。外源性 AREG 抑制 ILC2 细胞因子表达并增强 ST2 Treg 激活。此外，Areg 小鼠的 Treg 抑制 CD4 T 细胞活化的能力受损。此外，在疾病诱导之前应用外源性 IL-33 并不能保护缺乏 ST2 Treg 的 Foxp3Cre x ST2fl/fl 小鼠免受免疫介导的肝炎的影响。总之，我们描述了 ST2 Treg/AREG 轴在免疫介导的肝炎中的免疫调节作用，其中 AREG 抑制肝 ILC2 的激活，同时维持 ST2 Treg 并增强其在肝脏炎症中的免疫抑制能力。
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