Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure
Yan Zhang, Guoying Zhang, Brittany Dong, Ankit Pandeya, Jian Cui, Samuel Santos Valença, Ling Yang, Jiaqian Qi, Zhuodong Chai, Congqing Wu, Daniel Kirchhofer, Toshihiko Shiroishi, Fadi T. Khasawneh, Min Tao, Feng Shao, Christopher M. Waters, Yinan Wei, Zhenyu Li
Abstract
The NAIP/NLRC4 inflammasome plays a pivotal role in the defense against bacterial infections, with its in vivo physiological function primarily recognized as driving inflammation in immune cells. Acute lung injury (ALI) is a leading cause of mortality in sepsis. In this study, we identify that the NAIP/NLRC4 inflammasome is highly expressed in both macrophages and pulmonary fibroblasts and that pyroptosis of these cells plays a critical role in lung injury. Mice challenged with gram-negative bacteria or flagellin developed lethal lung injury, characterized by reduced blood oxygen saturation, disrupted lung barrier function, and escalated inflammation. Flagellin-induced lung injury was protected in caspase-1 or GSDMD-deficient mice. These findings enhance our understanding of the NAIP/NLRC4 inflammasome's (patho)physiological function and highlight the significant role of inflammasome activation and pyroptosis in ALI during sepsis.