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

被引:79
作者
Deng, Zhili [1 ,2 ,3 ,4 ,5 ]
Chen, Mengting [1 ,2 ,3 ,4 ,5 ]
Liu, Yingzi [1 ,2 ]
Xu, San [1 ,2 ,3 ,4 ]
Ouyang, Yuyan [1 ]
Shi, Wei [1 ]
Jian, Dan [1 ]
Wang, Ben [1 ]
Liu, Fangfen [1 ]
Li, Jinmao [1 ]
Shi, Qian [1 ]
Peng, Qinqin [1 ,4 ]
Sha, Ke [1 ,4 ]
Xiao, Wenqin [1 ,4 ]
Liu, Tangxiele [1 ,4 ]
Zhang, Yiya [1 ,2 ,3 ]
Zhang, Hongbing [6 ]
Wang, Qian [7 ]
Sun, Lunquan [1 ,3 ,4 ]
Xie, Hongfu [1 ,2 ,4 ,5 ]
Li, Ji [1 ,2 ,3 ,4 ,5 ,8 ]
机构
[1] Cent South Univ, Xiangya Hosp, Dept Dermatol, Changsha, Peoples R China
[2] Cent South Univ, Xiangya Hosp, Hunan Key Lab Aging Biol, Changsha, Peoples R China
[3] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha, Peoples R China
[4] Key Lab Mol Radiat Oncol Hunan Prov, Changsha, Peoples R China
[5] Cent South Univ, Key Lab Organ Injury Aging & Regenerat Med Hunan, Changsha, Peoples R China
[6] Chinese Acad Med Sci & Peking Union Med Coll, Inst Basic Med Sci, Dept Physiol, State Key Lab Med Mol Biol, Beijing, Peoples R China
[7] Hunan Binsis Biotechnol Co Ltd, Changsha, Peoples R China
[8] Xinjiang Med Univ, Dept Dermatol, Affiliated Hosp 2, Urumqi, Peoples R China
基金
中国国家自然科学基金;
关键词
LL37; mTOR; Rapamycin; rosacea; skin inflammation; NF-KAPPA-B; MAMMALIAN TARGET; RAPAMYCIN INHIBITORS; ATOPIC-DERMATITIS; PATHOPHYSIOLOGY; PATHOGENESIS; ACTIVATION; EXPRESSION; CANCER; CELLS;
D O I
10.15252/emmm.202013560
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页数:20
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