YAP/AP-1 Activation in Sebocytes Promotes CCL5-Dependent Perifollicular Macrophage Recruitment in Rosacea

Rosacea is a chronic inflammatory skin disorder in which macrophages have been increasingly implicated, yet the spatial basis and local cues of their recruitment remain poorly defined. Given the prominent perifollicular inflammatory changes in rosacea, we investigated whether sebocytes contribute to macrophage recruitment and the underlying mechanisms. Multiplex immunofluorescence combined with distance-stratified quantification demonstrated a preferential perifollicular distribution of macrophages around pilosebaceous units (PSUs) in human rosacea lesions. Integrated single-cell RNA sequencing and spatial transcriptomic analyses identified the C-C motif chemokine ligand 5 (CCL5)-C-C motif chemokine receptor 5 (CCR5) axis as a candidate mediator of sebocyte-macrophage crosstalk. Silencing CCL5 by small interfering RNA and CCL5 neutralization attenuated sebocyte-driven macrophage migration in vitro and reduced macrophage accumulation in vivo. Transcriptomic analysis of sebocytes further linked CCL5 expression to activation of Yes-associated protein (YAP)/activator protein-1 (AP-1) signaling. Consistently, pharmacological inhibition of YAP or AP-1 reduced CCL5 expression in sebocytes and alleviated erythema and macrophage infiltration in vivo. Furthermore, untargeted lipidomics uncovered profound metabolic reprogramming in sebocytes, characterized notably by the accumulation of cholesteryl esters. Bidirectional interventions via simvastatin and cholesterol loading confirmed that this lipid remodeling acts as an upstream driver of YAP nuclear translocation. Overall, our study identifies a PSU-centered inflammatory niche in rosacea and implicates lipid-driven, YAP/AP-1-associated sebocytic CCL5 upregulation in perifollicular macrophage recruitment, providing a rationale for further exploring sebocyte- and pilosebaceous unit-directed therapeutic strategies in rosacea.