Division of Pulmonary, Critical Care, Allergy & Sleep Medicine, University of California, San Francisco, California, USA.
Department of Internal Medicine, National Referral Center for Rare and Systemic Autoimmune Diseases, Cochin Hospital, AP-HP, Paris, France.
JCI Insight. 2021 Jun 22;6(12):143366. doi: 10.1172/jci.insight.143366.
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.
嗜酸性肉芽肿性多血管炎（EGPA）是一种罕见但严重的疾病，其发病机制尚未完全阐明。在这里，我们报告 EGPA 患者的 TSLP、IL-25 和可溶性 ST2 水平升高，这些都是经过充分研究的细胞因子“警报素”，可激活或调节 2 型固有淋巴细胞（ILC2）。活动期 EGPA 患者循环 ILC2 同时减少，提示 ILC2 在该疾病发病机制中起作用。为了探索这些发现的患者机制，我们建立了 EGPA 模型，通过在易感、高嗜酸性粒细胞小鼠中给予 IL-33 诱导活性血管炎和肺出血。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。在缺乏 IL4Rα 或 STAT6 的情况下，用 IL-33 处理的小鼠血管渗漏和肺水肿减少，内皮细胞激活减少，嗜酸性粒细胞趋化因子 eotaxin 产生减少，导致病理性嗜酸性粒细胞向肺实质迁移减少。这些结果为进一步研究 EGPA 的发病机制提供了一种小鼠模型，并提示 IL-33、ILC2 和 IL4Rα 信号可能是 EGPA 患者进一步研究和治疗靶向的潜在靶点。
