期刊
EMBO MOLECULAR MEDICINE
卷 13, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/emmm.202013560
关键词
LL37; mTOR; Rapamycin; rosacea; skin inflammation
资金
- National Natural Science Foundation of China [81874251, 82073457, 81673086, 81773351, 81974480]
- Science and Technology Innovation Plan of Hunan province [2018SK2087]
- Center for Molecular Medicine, Xiangya Hospital, Central South University, China
The study demonstrates that mTORC1 signaling is hyperactivated in the skin of rosacea patients and mouse model, blocking mTORC1 signaling can alleviate rosacea symptoms, while its hyperactivation can worsen the condition.
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-kappa B 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.
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