Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure

Authors

• Yan Zhang, Texas AandM University
• Guoying Zhang, Texas AandM University
• Brittany Dong, University of Kentucky College of MedicineFollow
• Ankit Pandeya, Texas AandM University
• Jian Cui, University of KentuckyFollow
• Samuel dos Santos Valenca, University of Kentucky College of Medicine
• Ling Yang, Texas AandM University
• Jiaqian Qi, Texas AandM University
• Zhuodong Chai, Texas AandM University
• Congqing Wu, University of KentuckyFollow
• Daniel Kirchhofer, Genentech Incorporated
• Toshihiko Shiroishi, RIKEN
• Fadi Khasawneh, Texas AandM University
• Min Tao, First Affiliated Hospital of Soochow University
• Feng Shao, National Institute of Biological Sciences, Beijing
• Christopher M. Waters, University of KentuckyFollow
• Yinan Wei, University of KentuckyFollow
• Zhenyu Li, University of KentuckyFollow

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.

Document Type

Article

Publication Date

4-22-2025

Notes/Citation Information

Publisher Copyright: © 2025 The Authors

Digital Object Identifier (DOI)

10.1016/j.celrep.2025.115479

Archival?

Archival

Repository Citation

Zhang, Yan; Zhang, Guoying; Dong, Brittany; Pandeya, Ankit; Cui, Jian; Valenca, Samuel dos Santos; Yang, Ling; Qi, Jiaqian; Chai, Zhuodong; Wu, Congqing; Kirchhofer, Daniel; Shiroishi, Toshihiko; Khasawneh, Fadi; Tao, Min; Shao, Feng; Waters, Christopher M.; Wei, Yinan; and Li, Zhenyu, "Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure" (2025). Chemistry Faculty Publications. 248.
https://uknowledge.uky.edu/chemistry_facpub/248