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

  • Cell Rep. 2025 Apr 22;44(4):115479. doi: 10.1016/j.celrep.2025.115479.
Yan Zhang  1 ,  Guoying Zhang  2 ,  Brittany Dong  3 ,  Ankit Pandeya  4 ,  Jian Cui  5 ,  Samuel Dos Santos Valenca  3 ,  Ling Yang  2 ,  Jiaqian Qi  2 ,  Zhuodong Chai  2 ,  Congqing Wu  6 ,  Daniel Kirchhofer  7 ,  Toshihiko Shiroishi  8 ,  Fadi Khasawneh  2 ,  Min Tao  9 ,  Feng Shao  10 ,  Christopher M Waters  11 ,  Yinan Wei  2 ,  Zhenyu Li  12
Affiliations
  • 1. Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA; Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
  • 2. Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA.
  • 3. Department of Physiology, University of Kentucky, Lexington, KY 40506, USA.
  • 4. Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA; Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
  • 5. Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40506, USA.
  • 6. Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40506, USA; Department of Surgery, University of Kentucky, Lexington, KY 40506, USA.
  • 7. Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA.
  • 8. RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan.
  • 9. Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
  • 10. National Institute of Biological Sciences, Beijing 102206 China.
  • 11. Department of Physiology, University of Kentucky, Lexington, KY 40506, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40506, USA.
  • 12. Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA. Electronic address: [email protected].
PMID: 40158217 DOI: 10.1016/j.celrep.2025.115479
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.

Keywords
CP: Immunology; inflammasome; lung injury; pyroptosis; sepsis.
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