A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary injury and repair.
A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary injury and repair.
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DOI：
10.1038/mi.2015.56
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发表时间：
2016-01
影响因子：
8
通讯作者：
Munitz A
中科院分区：
文献类型：
--
作者：
Karo-Atar D;Bordowitz A;Wand O;Pasmanik-Chor M;Fernandez IE;Itan M;Frenkel R;Herbert DR;Finkelman FD;Eickelberg O;Munitz A
调节肺纤维化中肺修复与进行性瘢痕形成的分子机制仍然难以捉摸。白细胞介素(IL)-4和IL-13是促纤维化细胞因子，具有包括IL-13受体(R) α1在内的共同受体链，是纤维化疾病的关键药理靶点。然而，IL-13Rα1在介导肺损伤/修复中的作用尚不清楚。我们报道了IL-13受体在博莱霉素治疗小鼠肺中的水平失调，并在一定程度上在特发性肺纤维化患者中。转录谱分析表明，上皮细胞相关的基因特征是稳态依赖于IL-13Rα1的表达。IL-13Rα1调节了博来霉素给药后肺部的一系列基因，Il13ra1缺乏导致博来霉素诱导的疾病加剧。博莱霉素处理的Il13ra1 - / -小鼠的病理增加是由于结构细胞和造血细胞中IL-13Rα1的表达，而不是由于对IL-17、IL-4、IL-13、IL-13Rα2或1型IL-4R信号的反应性增加。这些数据强调了IL-13Rα1在肺损伤和体内平衡中的保护作用。
Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1−/− mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.