Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure
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.
Authors
- Jiaqian Qi (ORCID: https://orcid.org/0000-0002-1613-4877)
- Ankit Pandeya (ORCID: https://orcid.org/0000-0002-7433-3129)
- Feng Shao
- Yinan Wei (ORCID: https://orcid.org/0000-0002-9936-7149)
- Congqing Wu (ORCID: https://orcid.org/0000-0001-7725-7881)
- Zhuodong Chai
- Samuel Santos Valença (ORCID: https://orcid.org/0000-0002-1868-9905)
- Toshihiko Shiroishi (ORCID: https://orcid.org/0000-0003-0535-2016)
- Daniel Kirchhofer (ORCID: https://orcid.org/0000-0002-0975-4402)
- Jian Cui (ORCID: https://orcid.org/0000-0002-8483-9975)
- Fadi T. Khasawneh (ORCID: https://orcid.org/0000-0002-4027-2997)
- Christopher M. Waters (ORCID: https://orcid.org/0000-0003-2336-7836)
- Yan Zhang (ORCID: https://orcid.org/0000-0003-0472-3399)
- Guoying Zhang (ORCID: https://orcid.org/0000-0001-9568-3702)
- Min Tao (ORCID: https://orcid.org/0000-0003-4139-7596)
- Ling Yang (ORCID: https://orcid.org/0009-0006-3974-6100)
- Zhenyu Li (ORCID: https://orcid.org/0009-0008-2180-1751)
- Brittany Dong
Institutions
- University of Kentucky (US)
- Soochow University (CN)
- National Institute of Biological Sciences, Beijing (CN)
- RIKEN BioResource Research Center (JP)
- First Affiliated Hospital of Soochow University (CN)
- Texas A&M University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1016/j.celrep.2025.115479
- Citations
- 9
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences