A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea

• Published in: EMBO molecular medicine Vol. 13; no. 5; pp. e13560 - n/a
• Main Authors: Deng, Zhili, Chen, Mengting, Liu, Yingzi, Xu, San, Ouyang, Yuyan, Shi, Wei, Jian, Dan, Wang, Ben, Liu, Fangfen, Li, Jinmao, Shi, Qian, Peng, Qinqin, Sha, Ke, Xiao, Wenqin, Liu, Tangxiele, Zhang, Yiya, Zhang, Hongbing, Wang, Qian, Sun, Lunquan, Xie, Hongfu, Li, Ji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-05-2021; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Ablation; Animals; Antimicrobial agents; Antimicrobial Cationic Peptides; Biopsy; Chemokines; Cytokines; Disease; EMBO19; EMBO38; Epidermis; Epithelium; Feedback; Genes; Humans; Inflammation; Keratinocytes; Kinases; LL37; Mammals; Mechanistic Target of Rapamycin Complex 1; Mice; mTOR; Pathogenesis; Patients; Protein synthesis; Proteins; Rapamycin; Rosacea; Rosacea - drug therapy; Skin diseases; skin inflammation; TLR2 protein; Toll-like receptors; Topical application; mTOR; Rapamycin; rosacea; skin inflammation; LL37
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202013560

Rosacea is a chronic inflammatory skin disorder whose pathogenesis is unclear. Here, several lines of evidence were provided to demonstrate that mTORC1 signaling is hyperactivated in the skin, especially in the epidermis, of both rosacea patients and a mouse model of rosacea‐like skin inflammation. Both mTORC1 deletion in epithelium and inhibition by its specific inhibitors can block the development of rosacea‐like skin inflammation in LL37‐induced rosacea‐like mouse model. Conversely, hyperactivation of mTORC1 signaling aggravated rosacea‐like features. Mechanistically, mTORC1 regulates cathelicidin through a positive feedback loop, in which cathelicidin LL37 activates mTORC1 signaling by binding to Toll‐like receptor 2 (TLR2) and thus in turn increases the expression of cathelicidin itself in keratinocytes. Moreover, excess cathelicidin LL37 induces both NF‐κB activation and disease‐characteristic cytokine and chemokine production possibly via mTORC1 signaling. Topical application of rapamycin improved clinical symptoms in rosacea patients, suggesting mTORC1 inhibition can serve as a novel therapeutic avenue for rosacea.
Synopsis
This study reveals a critical role of the positive feedback loop between mTORC1 signaling and cathelicidin in the pathogenesis of rosacea. Targeting mTORC1 may be a novel potential therapeutic strategy for rosacea treatment.
mTORC1 signaling is hyperactivated in the skin of rosacea patients and animal models.
Deletion or inhibition of mTORC1 suppresses the rosacea‐like skin inflammation in animal models.
Hyperactivation of mTORC1 aggravates the development of rosacea.
mTORC1 regulates cathelicidin via a positive feedback loop.
Cathelicidin LL37 induces NF‐κB signaling activation, and cytokines and chemokines production via mTORC1 signaling.
Graphical Abstract
This study reveals a critical role of the positive feedback loop between mTORC1 signaling and cathelicidin in the pathogenesis of rosacea. Targeting mTORC1 may be a novel potential therapeutic strategy for rosacea treatment.