Targeting Cannabinoid 1 Receptor in Macrophages Alleviates Psoriatic Skin Inflammation Through the AUF1-NLRP3 Axis

Psoriasis is a chronic inflammatory skin disease associated with systemic metabolic dysregulation; however, the molecular pathways linking metabolic signaling to skin inflammation remain poorly understood. Here, we identify cannabinoid 1 receptor (CB1R) in macrophages as a key immunometabolic regulator of psoriatic inflammation and a potential therapeutic target. CB1R expression was increased in macrophages infiltrating psoriatic lesional skin in both humans and mice, and both pharmacological inhibition and genetic deletion of CB1R markedly attenuated psoriasis-like pathology in mouse models by reducing epidermal hyperplasia, inflammation, and barrier dysfunction in a macrophage-dependent manner. Mechanistically, CB1R signaling in macrophages suppressed expression of the RNA-binding protein AUF1, leading to stabilization of Nlrp3 mRNA and enhanced NLRP3 inflammasome activation. AUF1 directly bound an AU-rich region within the Nlrp3 3' untranslated region and promoted mRNA destabilization, thereby limiting inflammasome activation and IL-1β production. Restoration of AUF1 expression, either by CB1R inhibition or overexpression, reduced NLRP3 levels and alleviated psoriasis-like pathology, whereas Nlrp3 deficiency abrogated these effects. Collectively, these findings define a CB1R-AUF1-NLRP3 signaling axis that links metabolic signaling to inflammasome-driven skin inflammation in macrophages. Targeting macrophage CB1R may therefore represent a promising therapeutic strategy for psoriasis and other immunometabolic inflammatory diseases.