Work

Nur77 Restrains Caspase-11-associated Macrophage Pyroptosis and Inflammatory Amplification During Early Sepsis

Year: 2026

Type: article

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.

Source: Inflammation

DOI: 10.1007/s10753-026-02568-6