Scopolamine ameliorates psoriasis by blocking M1 receptor-mediated IL-23 production in dendritic cells.

Psoriasis is a chronic inflammatory skin disease involving intricate neuroimmune crosstalk. However, the specific mechanisms and therapeutic targets remain elusive. In this study, a pilot clinical trial demonstrated that intravenous scopolamine, a muscarinic receptor antagonist, significantly ameliorated skin lesions in psoriasis patients. Consistently, scopolamine reduced inflammation in an imiquimod-induced mouse model. Metabolomic profiling identified acetylcholine (ACh) as a significantly upregulated neurotransmitter in psoriatic skin, and exogenous ACh exacerbated inflammatory phenotypes. To pinpoint the cellular target, single-cell RNA sequencing revealed that dendritic cells (DCs), unlike T cells or macrophages, uniquely coexpressed neurointeraction receptors and the pathogenic cytokine Il23a. Mechanistically, scopolamine competitively inhibited ACh binding to M1 muscarinic receptors (M1Rs) on DCs, suppressing interleukin (IL)-23 secretion. This therapeutic efficacy was recapitulated in mice with DC-specific M1R deletion. Crucially, the protective effect of M1R deficiency was abolished by recombinant IL-23 administration, whereas scopolamine failed to inhibit inflammation induced by direct IL-23 injection, confirming its action upstream of cytokine release. Collectively, our findings provide compelling evidence that scopolamine treats psoriasis by antagonizing elevated ACh and blocking M1 receptor-mediated IL-23 release in DCs.