A role for IL-33-activated ILC2s in eosinophilic vasculitis.
A role for IL-33-activated ILC2s in eosinophilic vasculitis.
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IL-33 激活的 ILC2 在嗜酸性血管炎中的作用。
DOI：
10.1172/jci.insight.143366
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Terrier,Benjamin
中科院分区：
文献类型：
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作者：
Kotas,MayaE;Dion,Jérémie;VanDyken,Steven;Ricardo-Gonzalez,RobertoR;Danel,ClaireJ;Taillé,Camille;Mouthon,Luc;Locksley,RichardM;Terrier,Benjamin
嗜酸性肉芽肿合并多血管炎(EGPA)是一种罕见但严重的疾病，其发病机制尚不清楚。在这里，我们报告了EGPA患者TSLP、IL-25和可溶性ST2水平的升高，这些都是激活或调节2型固有淋巴样细胞(ILC2s)的典型细胞因子“警报”。活动性EGPA患者循环中的ILC2s同时减少，提示ILC2s在本病的发病机制中起一定作用。为了探索这些发现在患者中的机制，我们建立了一个EGPA模型，在该模型中，使用IL-33诱导易患高嗜酸性粒细胞的小鼠发生活动性脉管炎和肺出血。在该模型中，肺出血和血管炎的诱导依赖于ILC2和通过IL4Rα的信号转导。在没有IL4Rα或STAT6的情况下，IL-33处理的小鼠血管渗漏和肺水肿较少，内皮激活较少，嗜酸性粒细胞产生减少，累积导致病理性嗜酸性粒细胞迁移到肺实质的减少。这些结果为未来EGPA的机制研究提供了一个小鼠模型，它们表明IL-33、ILC2和IL4Rα信号可能是进一步研究和治疗EGPA患者的潜在靶点。
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here, we report that patients with EGPA have elevated levels of TSLP, IL-25, and soluble ST2, which are well-characterized cytokine “alarmins” that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage were induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis was dependent on ILC2s and signaling through IL4Rα. In the absence of IL4Rα or STAT6, IL-33–treated mice had less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and they suggest that IL-33, ILC2s, and IL4Rα signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.