A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea
Abstract 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 infla...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202013560 |
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| author | Zhili Deng Mengting Chen Yingzi Liu San Xu Yuyan Ouyang Wei Shi Dan Jian Ben Wang Fangfen Liu Jinmao Li Qian Shi Qinqin Peng Ke Sha Wenqin Xiao Tangxiele Liu Yiya Zhang Hongbing Zhang Qian Wang Lunquan Sun Hongfu Xie Ji Li |
| author_facet | Zhili Deng Mengting Chen Yingzi Liu San Xu Yuyan Ouyang Wei Shi Dan Jian Ben Wang Fangfen Liu Jinmao Li Qian Shi Qinqin Peng Ke Sha Wenqin Xiao Tangxiele Liu Yiya Zhang Hongbing Zhang Qian Wang Lunquan Sun Hongfu Xie Ji Li |
| author_sort | Zhili Deng |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-3ba2bd93a87b4ead84cc1a7f5f5a666d |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-3ba2bd93a87b4ead84cc1a7f5f5a666d2025-08-20T04:03:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-03-0113512010.15252/emmm.202013560A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosaceaZhili Deng0Mengting Chen1Yingzi Liu2San Xu3Yuyan Ouyang4Wei Shi5Dan Jian6Ben Wang7Fangfen Liu8Jinmao Li9Qian Shi10Qinqin Peng11Ke Sha12Wenqin Xiao13Tangxiele Liu14Yiya Zhang15Hongbing Zhang16Qian Wang17Lunquan Sun18Hongfu Xie19Ji Li20Department of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityState Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeHunan Binsis Biotechnology Co.Department of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityAbstract 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.https://doi.org/10.15252/emmm.202013560LL37mTORRapamycinrosaceaskin inflammation |
| spellingShingle | Zhili Deng Mengting Chen Yingzi Liu San Xu Yuyan Ouyang Wei Shi Dan Jian Ben Wang Fangfen Liu Jinmao Li Qian Shi Qinqin Peng Ke Sha Wenqin Xiao Tangxiele Liu Yiya Zhang Hongbing Zhang Qian Wang Lunquan Sun Hongfu Xie Ji Li A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea EMBO Molecular Medicine LL37 mTOR Rapamycin rosacea skin inflammation |
| title | A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea |
| title_full | A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea |
| title_fullStr | A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea |
| title_full_unstemmed | A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea |
| title_short | A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea |
| title_sort | positive feedback loop between mtorc1 and cathelicidin promotes skin inflammation in rosacea |
| topic | LL37 mTOR Rapamycin rosacea skin inflammation |
| url | https://doi.org/10.15252/emmm.202013560 |
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