Fibroblast MrgprX2/B2 signaling, activated by LL37, drives hypertrophic scar fibrosis via TGF-β1.

Hypertrophic scarring (HTS) is a common clinical challenge characterized by excessive fibroblast activation and tissue fibrosis. Current treatments often fall short due to an incomplete understanding of the upstream signals driving pathological fibroblast proliferation. This study investigates the role of the G protein-coupled receptor MrgprX2 (human)/MrgprB2 (mouse), traditionally associated with mast cells, as a potential key mediator in fibroblast-driven fibrosis, addressing a critical gap in understanding HTS pathology.

Researchers investigated MrgprX2/B2's role in fibrosis using human dermal fibroblasts from HTS patients, humanized skin organoid models, and mouse studies. They assessed MrgprX2 upregulation in HTS fibroblasts and the effect of pharmacological inhibition of MrgprX2 on fibrosis in organoids. In mouse models, they identified the endogenous peptide LL37 as an MrgprX2/B2 activator, measuring its impact on calcium influx, TGF-β1 secretion, and fibroblast proliferation. Genetic ablation of MrgprB2 in fibroblasts was performed in vivo to confirm its role in fibrotic remodeling.

MrgprX2 was markedly upregulated in dermal fibroblasts isolated from HTS tissues. Pharmacological inhibition of MrgprX2 significantly reduced fibrosis in humanized skin organoid models. In mouse studies, the endogenous peptide LL37 emerged as an MrgprX2/B2 activator in fibroblasts, triggering calcium influx, transforming growth factor β1 (TGF-β1) secretion, and fibroblast proliferation. Genetic ablation of MrgprB2 in fibroblasts significantly reduced fibrosis in vivo, establishing a critical signaling axis.

The LL37-MrgprX2/B2-TGF-β1 axis was identified as a key mediator of fibroblast activation and fibrotic remodeling, linking tissue injury signals to fibrotic pathology.