Systemic administration of Neochamaejasmin B inhibits mast cell activation to reduce inflammation in a rosacea mouse model by targeting MRGPRX2

Rosacea is a chronic inflammatory disease characterised by facial erythema, telangiectasia, papules, pustules, and ocular manifestations. Mas-related G protein-coupled receptor X2 (MRGPRX2), suggested as a key receptor in the pathogenesis and inflammation of rosacea, is a potential therapeutic target to treat rosacea. Antibiotics are used to treat rosacea; however, drugs for targeted treatment are lacking. Few studies have investigated drugs that inhibit MRGPRX2 expression in rosacea. Neochamaejasmin B (NCB), the most abundant component in the dried roots of the toxic perennial herb Stellera chamaejasme L., exhibits various pharmacological activities, including anti-inflammatory effects. However, the pharmacological mechanism of NCB remains unclear. In this study, we investigated the effect of NCB on the inhibition of MRGPRX2 activation in an LL-37-induced rosacea mouse model. Hematoxylin and eosin staining, immunohistochemistry, and immunofluorescence staining were used to evaluate the effects of NCB on pathogenesis. Inflammatory mediators were measured using RNA Sequencing and enzyme-linked immunosorbent assay. The MRGPRX2-mediated mast cell (MC) degranulation model, molecular docking, molecular dynamics simulations, and surface plasmon resonance were used to evaluate the inhibitory effect of NCB on MRGPRX2. Finally, the downstream signalling pathway of MRGPRX2 was analyzed by western blotting. NCB reduced the pathogenesis and inflammation of rosacea in vivo by inhibiting MC activation and MRGPRX2-mediated MC activation in vitro. NCB showed a strong binding affinity for MRGPRX2 and inhibited NF-κB pathway activation. Our study showed that NCB reduced the pathogenesis and inflammation of rosacea by inhibiting MRGPRX2 activation.