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

7 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

Funding

We thank Andrew E. Hillhouse (Texas A&M University) for the scRNA analysis and Dr. Lijun Xia (Oklahoma Medical Research Foundation) and Dr. Xuyan Shi (National Institute of Biological Sciences, Beijing, China) for scientific inputs and critical feedback. The research was supported by the National Institutes of Health (R00HL145117 to C.W., R01 HL142640 and GM132443 to Y.W. and Z.L., R01HL146744 to Z.L., and R01 HL151419 and HL131526 to C.M.W.). Y.Z. is a recipient of the American Heart Association SouthWest Affiliate Postdoctoral Fellowship Award.

Funders	Funder number
American Heart Association SouthWest Affiliate
Oklahoma Medical Research Foundation
Andrew E. Hillhouse
Texas AandM University
National Institutes of Health (NIH)	R01 HL142640, R01 HL151419, R00HL145117, R01HL146744, HL131526, GM132443
National Institutes of Health (NIH)

Keywords

CP: Immunology
inflammasome
lung injury
pyroptosis
sepsis

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2025.115479

Cite this

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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title = "Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure",

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

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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

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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