Role of Type I Cannabinoid Receptor in Sensory Neurons in Psoriasiform Skin Inflammation and Pruritus.

Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and antipruritus effects against inflammation-based skin diseases, but the specific mechanism remains to be explored. In this study, we found that the activation of CB1R significantly relieved the scratching behavior and skin inflammation in a psoriatic mouse model, whereas CB1R antagonist aggravated these symptoms. Because the expression of CB1R was abundant in dorsal root ganglia, we constructed mice with conditional CB1R knockout in primary sensory neurons and found that imiquimod-induced psoriasiform inflammation and itch were both worsened in CB1R-conditional knockout mice. Next, we observed that the CB1R was mostly located in peptidergic neurons, and deletion of CB1R in primary sensory neurons promoted the production and release of substance P to the skin tissue. Furthermore, the elevated substance P in the skin affected the activation of extracellular signal‒regulated kinase in keratinocytes and induced the accumulation of mast cells in the dermis. Finally, we showed that blocking the substance P signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by imiquimod in CB1R-conditional knockout mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus by regulating substance P expression.