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 dos Santos Valenca; Ling Yang; Jiaqian Qi; Zhuodong Chai; Congqing Wu; Daniel Kirchhofer; Toshihiko Shiroishi; Fadi Khasawneh; Min Tao; Feng Shao; Christopher M. Waters; Yinan Wei; Zhenyu Li

doi:10.1016/j.celrep.2025.115479

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 dos Santos Valenca, Ling Yang, Jiaqian Qi, Zhuodong Chai, Congqing Wu, Daniel Kirchhofer, Toshihiko Shiroishi, Fadi Khasawneh, Min Tao, Feng Shao, Christopher M. Waters, Yinan Wei, Zhenyu Li

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	115479
Journal	Cell Reports
Volume	44
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2025.115479
State	Published - Apr 22 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

Keywords

CP: Immunology
inflammasome
lung injury
pyroptosis
sepsis

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2025.115479

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Zhang, Y., Zhang, G., Dong, B., Pandeya, A., Cui, J., Valenca, S. D. S., Yang, L., Qi, J., Chai, Z., Wu, C., Kirchhofer, D., Shiroishi, T., Khasawneh, F., Tao, M., Shao, F., Waters, C. M., Wei, Y., & Li, Z. (2025). Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure. Cell Reports, 44(4), Article 115479. https://doi.org/10.1016/j.celrep.2025.115479

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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.",

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author = "Yan Zhang and Guoying Zhang and Brittany Dong and Ankit Pandeya and Jian Cui and Valenca, {Samuel dos Santos} and Ling Yang and Jiaqian Qi and Zhuodong Chai and Congqing Wu and Daniel Kirchhofer and Toshihiko Shiroishi and Fadi Khasawneh and Min Tao and Feng Shao and Waters, {Christopher M.} and Yinan Wei and Zhenyu Li",

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Zhang, Y, Zhang, G, Dong, B, Pandeya, A, Cui, J, Valenca, SDS, Yang, L, Qi, J, Chai, Z, Wu, C, Kirchhofer, D, Shiroishi, T, Khasawneh, F, Tao, M, Shao, F, Waters, CM, Wei, Y & Li, Z 2025, 'Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure', Cell Reports, vol. 44, no. 4, 115479. https://doi.org/10.1016/j.celrep.2025.115479

TY - JOUR

T1 - Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure

AU - Zhang, Yan

AU - Zhang, Guoying

AU - Dong, Brittany

AU - Pandeya, Ankit

AU - Cui, Jian

AU - Valenca, Samuel dos Santos

AU - Yang, Ling

AU - Qi, Jiaqian

AU - Chai, Zhuodong

AU - Wu, Congqing

AU - Kirchhofer, Daniel

AU - Shiroishi, Toshihiko

AU - Khasawneh, Fadi

AU - Tao, Min

AU - Shao, Feng

AU - Waters, Christopher M.

AU - Wei, Yinan

AU - Li, Zhenyu

PY - 2025/4/22

Y1 - 2025/4/22

N2 - 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.

AB - 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.

KW - CP: Immunology

KW - inflammasome

KW - lung injury

KW - pyroptosis

KW - sepsis

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SN - 2639-1856

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JO - Cell Reports

JF - Cell Reports

IS - 4

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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