Merck & Co. Inc., Merck Research Laboratories, Palo Alto, CA 94304-1104, USA.
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Immunol. 2020 Apr 24;5(46). doi: 10.1126/sciimmunol.aav1080.
Signal transducer and activator of transcription (STAT) proteins have critical roles in the development and function of immune cells. STAT signaling is often dysregulated in patients with inflammatory bowel disease (IBD), suggesting the importance of STAT regulation during the disease process. Moreover, genetic alterations in and (e.g., deletions, mutations, and single-nucleotide polymorphisms) are associated with an increased risk for IBD. In this study, we elucidated the precise roles of STAT5 signaling in group 3 innate lymphoid cells (ILC3s), a key subset of immune cells involved in the maintenance of gut barrier integrity. We show that mice lacking either STAT5a or STAT5b are more susceptible to -mediated colitis and that interleukin-2 (IL-2)- and IL-23-induced STAT5 drives IL-22 production in both mouse and human colonic lamina propria ILC3s. Mechanistically, IL-23 induces a STAT3-STAT5 complex that binds IL-22 promoter DNA elements in ILC3s. Our data suggest that STAT5a/b signaling in ILC3s maintains gut epithelial integrity during pathogen-induced intestinal disease.
信号转导子和转录激活子（STAT）蛋白在免疫细胞的发育和功能中起着关键作用。STAT 信号在炎症性肠病（IBD）患者中常常失调，这表明在疾病过程中 STAT 调节的重要性。此外， 和 （例如缺失、突变和单核苷酸多态性）中的遗传改变与 IBD 的风险增加有关。在这项研究中，我们阐明了 STAT5 信号在 3 组固有淋巴细胞（ILC3）中的精确作用，ILC3 是参与维持肠道屏障完整性的关键免疫细胞亚群之一。我们表明，缺乏 STAT5a 或 STAT5b 的小鼠更容易发生 - 介导的结肠炎，并且白细胞介素 2（IL-2）和 IL-23 诱导的 STAT5 驱动小鼠和人结肠固有层 ILC3 中 IL-22 的产生。从机制上讲，IL-23 诱导 STAT3-STAT5 复合物，该复合物结合 ILC3 中的 IL-22 启动子 DNA 元件。我们的数据表明，ILC3 中的 STAT5a/b 信号在病原体诱导的肠道疾病中维持肠道上皮完整性。
