L-Arginine inhibits NLRP3 inflammasome activation

Nutritional status and metabolic homeostasis are intricately associated with the inflammatory response. However, the direct mechanistic link between nutrition, metabolism and inflammation remains unclear. Here, we show that the amino acid L-arginine (L-Arg) is a potent endogenous inhibitor of the NLRP3 inflammasome, a central component of the inflammatory signalling pathway. We show that L-Arg binds directly to the Asp31 site of the NLRP3 protein, blocking its interaction with the adaptor ASC and subsequent inflammasome assembly and activation. L-Arg supplementation inhibits the NLRP3 inflammasome activation in macrophages, while deprivation promotes it. Treatment with L-Arg in mice alleviates monosodium urate crystal-induced arthritis and aluminium-induced peritonitis. In addition, L-Arg supplementation alleviates neuroinflammation and motor deficits in mouse models of Parkinson's disease, whereas L-Arg deprivation exacerbates pathology. In patients with Parkinson's disease, L-Arg levels are reduced in serum. Our study establishes L-Arg supplementation as a promising therapeutic avenue for managing NLRP3-driven inflammatory pathologies.