2. Academic Validation
  3. Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure

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

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: zli21@tamu.edu.
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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