Singh Priti B, Pua Heather H, Happ Hannah C, Schneider Christoph, von Moltke Jakob, Locksley Richard M, Baumjohann Dirk, Ansel K Mark
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA.
Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA.
J Exp Med. 2017 Dec 4;214(12):3627-3643. doi: 10.1084/jem.20170545. Epub 2017 Nov 9.
MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (T2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17∼92-deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17∼92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and T2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses.
微小RNA（miRNA）通过对多种细胞中多个靶基因的协同调控，对免疫发挥强大作用。2型天然淋巴细胞（ILC2）是过敏性炎症的组织哨兵介质。我们确定了ILC2稳态和免疫功能中miRNA的生理需求，并比较了静息和活化的ILC2以及2型辅助性T细胞（T2）的整体miRNA谱。在接触天然过敏原木瓜蛋白酶后，ILC2中选择性缺失miR-17∼92簇的小鼠肺部炎症减轻。此外，miR-17∼92缺陷的ILC2在体外对IL-33和胸腺基质淋巴细胞生成素的反应中表现出生长缺陷和细胞因子表达缺陷。miR-17∼92簇成员miR-19a促进IL-13和IL-5的产生，并抑制包括SOCS1和A20在内的几个靶标的表达，这些信号抑制剂会限制IL-13和IL-5的产生。这些发现确立了miRNA作为ILC2生物学的重要调节因子，揭示了ILC2和T2细胞中重叠但不完全相同的miRNA调节基因表达网络，并增强了靶向miR-19以减轻致病性过敏反应的治疗潜力。
