Nur77 Restrains Caspase-11-associated Macrophage Pyroptosis and Inflammatory Amplification During Early Sepsis
- 1¹Department of Intensive Care Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550004 China
- 2²Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Ankang Avenue, Guian New District, Guizhou, 561113 China
- 3³Key Laboratory for Research on Autoimmune Diseases of Higher Education Schools in Guizhou Province, 6 Ankang Avenue, Guian New District, Guizhou, 561113 China
Abstract
Noncanonical inflammasome activation mediated by caspase-11 drives macrophage pyroptosis and inflammatory amplification in sepsis, but endogenous restraining mechanisms remain incompletely understood. Here, we investigated the role of Nur77 (NR4A1) in cytosolic LPS-induced pyroptotic signaling using RAW264.7 macrophages and an early cecal ligation and puncture (CLP) sepsis model. LPS priming followed by cytosolic LPS stimulation increased Nur77 expression, caspase-11 cleavage, GSDMD processing, lactate dehydrogenase release, and IL-1β release. Nur77 knockdown aggravated membrane damage, increased GSDMD-N generation and pyroptosis-associated cells, and enhanced IL-1β and IL-18 release. Conversely, Nur77 overexpression attenuated caspase-11/GSDMD-associated readouts and reduced pyroptosis-associated injury. This stimulation condition also increased pannexin-1 and P2 × 7 expression, extracellular ATP release, and Yo-PRO-1 uptake; and these changes were amplified by Nur77 deficiency and blunted by Nur77 overexpression. Wedelolactone treatment attenuated caspase-11-associated readouts and was accompanied by reduced pannexin-1/P2 × 7-related responses. In vivo, pharmacological modulation of Nur77 in the early CLP model was associated with corresponding changes in systemic IL-1β/IL-18 levels, lung, liver, and kidney injury, and caspase-11/GSDMD-associated readouts. Collectively, these findings support a model in which Nur77 acts as an endogenous negative modulator of caspase-11/GSDMD-associated pyroptotic signaling and inflammatory amplification during early sepsis.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10753-026-02568-6.
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BibTeX
@article{yang2026nur77,
title = {{Nur77 Restrains Caspase-11-associated Macrophage Pyroptosis and Inflammatory Amplification During Early Sepsis}},
author = {Changzhen Yang and Jiakai Wang and Hongying Bi and Jianyu Fu and Xian Liu and Min Su and Xu Liu},
journal = {Inflammation},
year = {2026},
month = aug,
doi = {10.1007/s10753-026-02568-6},
url = {https://doi.org/10.1007/s10753-026-02568-6},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Nur77 Restrains Caspase-11-associated Macrophage Pyroptosis and Inflammatory Amplification During Early Sepsis
AU - Changzhen Yang
AU - Jiakai Wang
AU - Hongying Bi
AU - Jianyu Fu
AU - Xian Liu
AU - Min Su
AU - Xu Liu
PY - 2026
DA - 2026/08/08
JO - Inflammation
DO - 10.1007/s10753-026-02568-6
UR - https://doi.org/10.1007/s10753-026-02568-6
AB - Noncanonical inflammasome activation mediated by caspase-11 drives macrophage pyroptosis and inflammatory amplification in sepsis, but endogenous restraining mechanisms remain incompletely understood. Here, we investigated the role of Nur77 (NR4A1) in cytosolic LPS-induced pyroptotic signaling using RAW264.7 macrophages and an early cecal ligation and puncture (CLP) sepsis model. LPS priming followed by cytosolic LPS stimulation increased Nur77 expression, caspase-11 cleavage, GSDMD processing, lactate dehydrogenase release, and IL-1β release. Nur77 knockdown aggravated membrane damage, increased GSDMD-N generation and pyroptosis-associated cells, and enhanced IL-1β and IL-18 release. Conversely, Nur77 overexpression attenuated caspase-11/GSDMD-associated readouts and reduced pyroptosis-associated injury. This stimulation condition also increased pannexin-1 and P2 × 7 expression, extracellular ATP release, and Yo-PRO-1 uptake; and these changes were amplified by Nur77 deficiency and blunted by Nur77 overexpression. Wedelolactone treatment attenuated caspase-11-associated readouts and was accompanied by reduced pannexin-1/P2 × 7-related responses. In vivo, pharmacological modulation of Nur77 in the early CLP model was associated with corresponding changes in systemic IL-1β/IL-18 levels, lung, liver, and kidney injury, and caspase-11/GSDMD-associated readouts. Collectively, these findings support a model in which Nur77 acts as an endogenous negative modulator of caspase-11/GSDMD-associated pyroptotic signaling and inflammatory amplification during early sepsis. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10753-026-02568-6.
SN - 0360-3997
SN - 1573-2576
ER -