Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China.
EMBO Mol Med. 2021 May 7;13(5):e13560. doi: 10.15252/emmm.202013560. Epub 2021 Mar 18.
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.
酒渣鼻是一种慢性炎症性皮肤疾病，其发病机制尚不清楚。本研究提供了一些证据表明，mTORC1 信号在酒渣鼻患者和类似酒渣鼻皮肤炎症的小鼠模型的皮肤中，特别是表皮中过度激活。上皮细胞中 mTORC1 的缺失和其特异性抑制剂的抑制均可阻断 LL37 诱导的类似酒渣鼻的小鼠模型中类似酒渣鼻的皮肤炎症的发展。相反，mTORC1 信号的过度激活加重了类似酒渣鼻的特征。在机制上，mTORC1 通过正反馈回路调节抗菌肽，其中抗菌肽 LL37 通过与 Toll 样受体 2（TLR2）结合来激活 mTORC1 信号，从而反过来增加角质形成细胞中抗菌肽本身的表达。此外，多余的抗菌肽 LL37 通过 mTORC1 信号诱导 NF-κB 激活和疾病特征性细胞因子和趋化因子的产生。雷帕霉素的局部应用改善了酒渣鼻患者的临床症状，表明 mTORC1 抑制可作为酒渣鼻的一种新的治疗途径。
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