Activation of hippo signaling pathway enhances CCL5 secretion in sebocytes and induces macrophage infiltration in rosacea

Summary: Abstract Body: Rosacea is a chronic inflammatory skin disease characterized by the involvement of pilosebaceous units (PSUs) and capillaries. Macrophages constitute a significant portion of the infiltrating cells in rosacea. However, the mechanisms underlying the recruitment of macrophages to rosacea lesions are not well understood, and their interactions with structural cutaneous cells, as well as the precise molecular pathways involved, require further investigation. We investigated macrophage infiltration patterns in rosacea using human biopsy specimens and CX3CR-1GFP knock-in mice. Single-cell RNA sequencing, RNAscope, and ELISA were employed to examine the interactions between sebocytes and macrophages. YAP localization was assessed via immunofluorescence and Western blot to verify the activation of Hippo and AP-1 signaling. Subsequently, we performed in vivo blockade of Hippo and AP-1 signaling using verteporfin and SR11302 to explore their regulatory role in CCL5 secretion and macrophage infiltration. In rosacea lesions, macrophages infiltrated in a perifollicular pattern, providing spatial evidence for interactions between PSUs and macrophages. LL37 enhanced the secretion of CCL5 in sebocytes, with the CCL5/CCR5 axis mediating the interaction between sebocytes and macrophages. Transcriptomics results also suggested the activation of Hippo and AP-1 signaling in rosacea, which was confirmed by the increased YAP nuclear localization and upregulation of FOSB protein expression in sebocytes treated with LL37. Meanwhile, the blockade of Hippo and AP-1 signaling reduced macrophage infiltration and attenuated rosacea-like skin inflammation in vivo. These findings elucidate that the activation of the Hippo pathway in sebocytes promotes CCL5 secretion and recruitment of macrophages, thereby inducing rosacea inflammation. This underscores the crucial role of sebocytes in the progression of rosacea and provides insights for developing therapies targeting sebocytes. Jia Liu¹, Jin Yang¹, Peiru Wang¹, Xiuli Wang¹, Qingyu Zeng¹ 1. Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, Shanghai, China. Cell Communication Networks and Stromal Biology