Neurotransmitter 5-HT Further Promotes LL-37-Induced Rosacea-like Inflammation Through HTR3A

Rosacea is a chronic inflammatory skin disease and is usually accompanied by extensive macrophage infiltration. There is growing evidence suggesting that neurotransmitter 5-hydroxytryptamine (5-HT) plays a crucial role in inflammatory reactions. However, the interaction between 5-HT and rosacea is still unclear. Here, we hypothesized that the inflammation of rosacea is partly caused by 5-HT, and we investigated the underlying mechanism. In this study, we employed a rosacea model induced by LL-37, which is usually applicated as a rosacea stimulator, to investigate the effects of 5-HT on rosacea in vitro and in vivo. In LL-37-(4 μM)-induced THP-1-derived macrophages, 5-HT (400 μM) further promoted the secretion of inflammatory cytokines and polarized macrophages towards M1 phenotype, which could promote an inflammatory response. Further research revealed that exposure to LL-37 and 5-HT (L5) selectively upregulated <i>HTR3A</i> mRNA expression but not <i>HTR2A</i> or <i>HTR7</i> and induced colocalization of 5-HT with HTR3A. Notably, application of antagonist tropisetron (TPS) and siRNA of <i>HTR3A</i> suppressed L5-induced inflammation. Meanwhile, 5-HT (25 μg each injection a total of three times) deteriorated skin erythema, stimulated dermal inflammatory cell infiltration, and promoted the secretion of inflammatory cytokines in LL-37 (40 μL and 320 μM each injection a total of four times) induced rosacea-like mice, while these undesirable effects were reversed by using TPS. Our findings revealed that neurotransmitter 5-HT further promoted LL-37-induced rosacea-like inflammation through HTR3A. Our study highlights HTR3A as a promising therapeutic target, which warrants further in-depth investigation into its clinical applicability.