Quinolinic Acid, a Tryptophan Metabolite of the Skin Microbiota, Negatively Regulates NLRP3 Inflammasome through AhR in Psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease whose pathogenesis involves skin microbiota dysbiosis. Multiple studies have revealed the changes in microbiota abundances between psoriatic lesions and healthy skin. However, the metabolic pathways of skin microbiota (especially tryptophan metabolism, which is closely related to immunosuppression) are far less understood. In this study, we first detected the major microbial metabolites of tryptophan on the skin surfaces, finding that the quinolinic acid was significantly lower in the lesional skin of patients with psoriasis than in that of healthy subjects and correlated negatively with the severity of psoriasis. Invitro and invivo, applying quinolinic acid significantly alleviated skin inflammation in an AhR-dependent manner, resulting in inhibition of the NLRP3 inflammasome activation. Furthermore, in mice with imiquimod-induced psoriasis-like dermatitis, topical application of Ahr-targeted small interfering RNA substantially exacerbated the disease severity, with increased NLRP3 inflammasome activation. Collectively, our data suggest that quinolinic acid, a skin microbiota-derived metabolite, negatively regulates aryl hydrocarbon receptor-NLRP3 inflammasome signaling activation in patients with psoriasis, providing an insight into the correlation between microbiota metabolism and the host skin in individuals with psoriasis.