Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Immunity. 2023 May 9;56(5):1115-1131.e9. doi: 10.1016/j.immuni.2023.02.018. Epub 2023 Mar 13.
Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.
肠道中产生白细胞介素 17 的辅助性 T 细胞（Th17 细胞）的发育依赖于肠道内黏附的微生物。然而，微生物黏附到肠上皮细胞（IEC）如何促进 Th17 细胞分化仍然是一个谜。在这里，我们发现诱导 Th17 细胞的肠道细菌会在 IEC 中引发未折叠蛋白反应（UPR）。此外，在 IEC 中表达枯草溶菌素细胞毒素或基因敲除 X 盒结合蛋白 1（Xbp1）会引发 UPR 并增加 Th17 细胞，即使在使用抗生素或无菌条件下也是如此。从机制上讲，IEC 中 UPR 的激活增强了它们产生活性氧（ROS）和嘌呤代谢物的能力。用 N-乙酰半胱氨酸或别嘌呤醇处理小鼠以分别减少 ROS 和黄嘌呤的产生，可减少与 UPR 升高相关的 Th17 细胞。与炎症性肠病患者相关的 Th17 相关基因也与 ER 应激和 UPR 相关。总的来说，我们确定了一种源自 IEC 相关 UPR 的肠道 Th17 细胞分化机制。
