Gut-derived memory γδ T17 cells exacerbate sepsis-induced acute lung injury in mice
Bing Xie, Mengyuan Wang, Xinyu Zhang, Yujing Zhang, Hong Qi, Hong Liu, Yuming Wu, Xiaoyue Wen, Xiaoyan Chen, Mengqi Han, Dan Xu, Xueqiang Sun, Xue Zhang, Xin Zhao, You Shang, Shiying Yuan, Jiancheng Zhang
Abstract
Sepsis is a critical global health concern linked to high mortality rates, often due to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). While the gut-lung axis involvement in ALI is recognized, direct migration of gut immune cells to the lung remains unclear. Our study reveals sepsis-induced migration of γδ T17 cells from the small intestine to the lung, triggering an IL-17A-dominated inflammatory response in mice. Wnt signaling activation in alveolar macrophages drives CCL1 upregulation, facilitating γδ T17 cell migration. CD44+ Ly6C– IL-7Rhigh CD8low cells are the primary migratory subtype exacerbating ALI. Esketamine attenuates ALI by inhibiting pulmonary Wnt/β-catenin signaling-mediated migration. This work underscores the pivotal role of direct gut-to-lung memory γδ T17 cell migration in septic ALI and clarifies the importance of localized IL-17A elevation in the lung. Sepsis can result in acute lung injury which may involve cross interaction via the gut-lung axis. Here the authors show γδ T17 cell migration from the gut to the lung in a murine model of sepsis and link IL-17A-mediated lung inflammation regulation by Wnt/β-catenin signaling in alveolar macrophages via CCL1.