A Proinflammatory Role of Type 2 Innate Lymphoid Cells in Murine Immune-Mediated Hepatitis
A Proinflammatory Role of Type 2 Innate Lymphoid Cells in Murine Immune-Mediated Hepatitis
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DOI：
10.4049/jimmunol.1600418
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Tiegs, Gisa
中科院分区：
文献类型：
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作者：
Neumann, Katrin;Karimi, Khalil;Tiegs, Gisa
2 型先天淋巴细胞 (ILC2) 在警报蛋白 IL-33 引发的疾病中介导炎症免疫反应。近年来，IL-33被认为与免疫介导的肝病的发病机制有关。然而，ILC2 在发炎肝脏中的免疫调节功能仍然难以捉摸。使用Con A诱导的免疫介导的肝炎的小鼠模型，我们发现肝脏中ILC2的选择性扩增与肝脏IL-33表达高度升高、严重的肝脏炎症和嗜酸性粒细胞浸润相关。 CD4（+）T细胞介导的组织损伤和随后的IL-33释放是导致肝脏ILC2激活的原因，ILC2在肝脏炎症期间产生2型细胞因子IL-5和IL-13。有趣的是，ILC2耗竭与肝炎的严重程度减轻和肝脏中嗜酸性粒细胞的积累减少相关，而肝脏ILC2的过继转移则加剧了肝脏炎症和组织损伤。我们进一步表明，尽管肝脏 ILC2 扩增，Con A 攻击前 3 天的 IL-33 治疗可有效抑制免疫介导的肝炎的发展。我们发现IL-33不仅激活肝脏ILC2，而且还扩增肝脏中表达IL-33受体ST2的CD4(+) Foxp(3+)调节性T细胞(Treg)。在免疫介导的肝炎消退过程中，该 Treg 亚群也在肝脏中积累。总之，肝脏 ILC2 准备通过 2 型细胞因子的表达来响应肝组织损伤时 IL-33 的释放，从而参与免疫介导的肝炎的发病机制。 ILC2 的炎症活性可能受到 IL-33 引发的 ST2(+) Tregs 的调节，ST2(+) Tregs 也出现在免疫介导的肝炎中。
Type 2 innate lymphoid cells (ILC2) mediate inflammatory immune responses in the context of diseases triggered by the alarmin IL-33. In recent years, IL-33 has been implicated in the pathogenesis of immune-mediated liver diseases. However, the immunoregulatory function of ILC2s in the inflamed liver remains elusive. Using the murine model of Con A-induced immune-mediated hepatitis, we showed that selective expansion of ILC2s in the liver was associated with highly elevated hepatic IL-33 expression, severe liver inflammation, and infiltration of eosinophils. CD4(+) T cell-mediated tissue damage and subsequent IL-33 release were responsible for the activation of hepatic ILC2s that produced the type 2 cytokines IL-5 and IL-13 during liver inflammation. Interestingly, ILC2 depletion correlated with less severe hepatitis and reduced accumulation of eosinophils in the liver, whereas adoptive transfer of hepatic ILC2s aggravated liver inflammation and tissue damage. We further showed that, despite expansion of hepatic ILC2s, 3-d IL-33 treatment before Con A challenge potently suppressed development of immune-mediated hepatitis. We found that IL-33 not only activated hepatic ILC2s but also expanded CD4(+) Foxp(3+) regulatory T cells (Treg) expressing the IL-33 receptor ST2 in the liver. This Treg subset also accumulated in the liver during resolution of immune-mediated hepatitis. In summary, hepatic ILC2s are poised to respond to the release of IL-33 upon liver tissue damage through expression of type 2 cytokines thereby participating in the pathogenesis of immune-mediated hepatitis. Inflammatory activity of ILC2s might be regulated by IL-33-elicited ST2(+) Tregs that also arise in immune-mediated hepatitis.