Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis
Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis
复制标题
DOI：
10.1016/j.immuni.2018.04.023
复制
发表时间：
2018-07-17
期刊：
影响因子：
32.4
通讯作者：
Nakayama, Toshinori
中科院分区：
文献类型：
--
作者：
Morimoto, Yuki;Hirahara, Kiyoshi;Nakayama, Toshinori
记忆T细胞提供持久的保护性免疫，记忆T细胞的不同亚群推动慢性炎症性疾病，如哮喘。哮喘是一种慢性过敏性炎症性疾病，伴有包括纤维化改变在内的气道重塑。诱导呼吸道纤维化改变的免疫学机制尚不清楚。我们发现，白介素33(IL-33)可促进IL-33受体ST2(Hi)记忆T辅助细胞(Th2)产生双调节素。双调蛋白-表皮生长因子受体(EGFR)介导的信号直接将嗜酸性粒细胞重新编程为炎症状态，增加了骨桥蛋白的产生，骨桥蛋白是一种关键的促纤维化免疫调节蛋白。产生IL-5的记忆Th2细胞和产生双调节蛋白的记忆Th2细胞似乎在建立肺纤维化方面协同作用。慢性嗜酸性鼻窦炎患者的息肉分析显示纤维化，聚集有产生双调节蛋白的CRTH2(Hi)、CD161(Hi)、CD45RO(+)、CD4(+)Th2细胞和产生骨桥蛋白的嗜酸性粒细胞。因此，IL-33-Am-phiRegin-Osteopontin轴在嗜酸性气道炎症中引导纤维化反应，是治疗慢性变态反应性疾病引起的纤维化的潜在靶点。
Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2(hi) memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2(hi) CD161(hi) CD45RO(+)CD4(+) Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-am-phiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.