NLRP3 Senses L-Arginine to Inhibit Inflammasome Activation and Alleviate Parkinson’s disease Pathology

ABSTRACT:

We screened a series of metabolites and found that L-Arg strongly inhibits NLRP3 inflammasome assembly in vitro. Mechanistically, L-Arg directly binds the D31 site of NLRP3, blocking NLRP3-ASC interaction and subsequent inflammasome assembly. This discovery establishes NLRP3 as a direct sensor for L-Arg. Additionally, L-Arg supplementation inhibits NLRP3 inflammasome activation in macrophages, while deprivation promotes it. Treatment with L-Arg in mice alleviates the MSU-induced arthritis and Alum-induced peritonitis. These findings reveal a new link between L-Arg metabolic homeostasis and inflammasome activation under physiological conditions. Moreover, we show decreased serum L-Arg levels in PD patients. In PD mouse models, L-Arg supplementation alleviates disease symptoms by modulating the NLRP3 inflammasome, whereas an L-Arg-deficient diet conversely exacerbates them. Our study uncovers a novel function of NLRP3 as a sensor for amino acid metabolism and demonstrates the new mechanism by which L-Arg regulates NLRP3 inflammasome activation, thereby offering a novel potential therapeutic strategy for inflammasome-related diseases.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic

PROVIDER: MTBLS13737 | MetaboLights | 2026-09-02

REPOSITORIES: MetaboLights