Gut-derived memory γδ T17 cells exacerbate sepsis-induced acute lung injury in mice

• Published in: Nature communications Vol. 15; no. 1; pp. 6737 - 16
• Main Authors: Xie, Bing, Wang, Mengyuan, Zhang, Xinyu, Zhang, Yujing, Qi, Hong, Liu, Hong, Wu, Yuming, Wen, Xiaoyue, Chen, Xiaoyan, Han, Mengqi, Xu, Dan, Sun, Xueqiang, Zhang, Xue, Zhao, Xin, Shang, You, Yuan, Shiying, Zhang, Jiancheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 13/89; 13/95; 14/1; 14/63; 631/250/1619/554/2509; 631/250/255/1318; 631/250/347; 64/110; 64/60; 692/699/255/1318; 82/47; 82/80; 96/21; Acute Lung Injury - immunology; Acute Lung Injury - pathology; Alveoli; Animal models; Animals; Antigens, Ly - metabolism; CD44 antigen; Cell activation; Cell adhesion & migration; Cell Movement; Chemokines; Digestive system; Disease Models, Animal; Gastrointestinal tract; Global health; Humanities and Social Sciences; Immune system; Immunologic Memory; Immunological memory; Inflammation; Inflammatory response; Injuries; Interleukin-17 - immunology; Interleukin-17 - metabolism; Intestine; Intestine, Small - immunology; Intestine, Small - pathology; Intraepithelial Lymphocytes - immunology; Leukocyte migration; Lung - immunology; Lung - pathology; Lungs; Macrophages; Macrophages, Alveolar - immunology; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Public health; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Respiratory distress syndrome; Science; Science (multidisciplinary); Sepsis; Sepsis - complications; Sepsis - immunology; Small intestine; Wnt protein; Wnt Signaling Pathway - immunology; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51209-9

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-7R high CD8 low 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.