A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages
BackgroundRosacea, a chronic inflammatory skin disorder etiologically associated with immune cells and the antibacterial peptide cathelicidin LL-37, can be effectively treated by oral carvedilol administration.ObjectiveTo investigate the molecular mechanisms underlying carvedilol efficacy in rosacea...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.609615/full |
| _version_ | 1819121054101012480 |
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| author | Jiawen Zhang Peiyu Jiang Lei Sheng Yunyi Liu Yixuan Liu Min Li Meng Tao Liang Hu Xiaoyan Wang Yanjing Yang Yang Xu Wentao Liu |
| author_facet | Jiawen Zhang Peiyu Jiang Lei Sheng Yunyi Liu Yixuan Liu Min Li Meng Tao Liang Hu Xiaoyan Wang Yanjing Yang Yang Xu Wentao Liu |
| author_sort | Jiawen Zhang |
| collection | DOAJ |
| description | BackgroundRosacea, a chronic inflammatory skin disorder etiologically associated with immune cells and the antibacterial peptide cathelicidin LL-37, can be effectively treated by oral carvedilol administration.ObjectiveTo investigate the molecular mechanisms underlying carvedilol efficacy in rosacea treatment.MethodsSkin samples of patients with rosacea were subjected to histopathological (hematoxylin and eosin) and immunohistochemical (CD68, Toll-like receptor 2 (TLR2), kallikrein 5, cathelicidin, TNF-α, and IL-1β) evaluation. An in vivo murine rosacea-like inflammation model was established by LL-37 intradermal injection with or without carvedilol gavage-based pretreatment. Erythema proportion (Image J) and skin redness (L*a*b colorimetry) were quantified. Murine skin samples underwent pathological examination for inflammatory status and immunofluorescence staining. Murine skin and lipopolysaccharide-stimulated RAW 264.7 cells with or without carvedilol pretreatment were evaluated by quantitative reverse transcription-polymerase chain reaction and western blotting. Clinical facial images of patients were obtained using the VISIA skin analysis system before, 4, and 6 months following oral carvedilol administration.ResultsRosacea skin lesions exhibited more pronounced inflammatory cell infiltration than peripheral areas, with profound macrophage infiltration and inflammatory cytokines (TLR2, kallikrein 5, cathelicidin, TNF-α, and IL-1β). In vivo, carvedilol alleviated inflammation in LL-37 mice, down-regulating TLR2, KLK5, and cathelicidin expression. In vitro, carvedilol decreased TLR2 expression in RAW 264.7 cells, further reducing KLK5 secretion and LL-37 expression and ultimately inhibiting rosacea-like inflammatory reactions. Clinical manifestations and facial redness obviously improved during 6-month follow-up with systemic carvedilol administration.ConclusionCarvedilol is effective against rosacea, with inhibition of macrophage TLR2 expression as a novel anti-inflammatory mechanism. |
| first_indexed | 2024-12-22T06:30:27Z |
| format | Article |
| id | doaj.art-27ee668ca09447b0aa2b565b78989f8c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T06:30:27Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-27ee668ca09447b0aa2b565b78989f8c2022-12-21T18:35:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.609615609615A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in MacrophagesJiawen Zhang0Peiyu Jiang1Lei Sheng2Yunyi Liu3Yixuan Liu4Min Li5Meng Tao6Liang Hu7Xiaoyan Wang8Yanjing Yang9Yang Xu10Wentao Liu11Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaJiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, ChinaDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaJiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, ChinaDepartment of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, ChinaJiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, ChinaDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaJiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, ChinaBackgroundRosacea, a chronic inflammatory skin disorder etiologically associated with immune cells and the antibacterial peptide cathelicidin LL-37, can be effectively treated by oral carvedilol administration.ObjectiveTo investigate the molecular mechanisms underlying carvedilol efficacy in rosacea treatment.MethodsSkin samples of patients with rosacea were subjected to histopathological (hematoxylin and eosin) and immunohistochemical (CD68, Toll-like receptor 2 (TLR2), kallikrein 5, cathelicidin, TNF-α, and IL-1β) evaluation. An in vivo murine rosacea-like inflammation model was established by LL-37 intradermal injection with or without carvedilol gavage-based pretreatment. Erythema proportion (Image J) and skin redness (L*a*b colorimetry) were quantified. Murine skin samples underwent pathological examination for inflammatory status and immunofluorescence staining. Murine skin and lipopolysaccharide-stimulated RAW 264.7 cells with or without carvedilol pretreatment were evaluated by quantitative reverse transcription-polymerase chain reaction and western blotting. Clinical facial images of patients were obtained using the VISIA skin analysis system before, 4, and 6 months following oral carvedilol administration.ResultsRosacea skin lesions exhibited more pronounced inflammatory cell infiltration than peripheral areas, with profound macrophage infiltration and inflammatory cytokines (TLR2, kallikrein 5, cathelicidin, TNF-α, and IL-1β). In vivo, carvedilol alleviated inflammation in LL-37 mice, down-regulating TLR2, KLK5, and cathelicidin expression. In vitro, carvedilol decreased TLR2 expression in RAW 264.7 cells, further reducing KLK5 secretion and LL-37 expression and ultimately inhibiting rosacea-like inflammatory reactions. Clinical manifestations and facial redness obviously improved during 6-month follow-up with systemic carvedilol administration.ConclusionCarvedilol is effective against rosacea, with inhibition of macrophage TLR2 expression as a novel anti-inflammatory mechanism.https://www.frontiersin.org/articles/10.3389/fimmu.2021.609615/fullrosaceacarvedilolmacrophageTLR2KLK5cathelicidin |
| spellingShingle | Jiawen Zhang Peiyu Jiang Lei Sheng Yunyi Liu Yixuan Liu Min Li Meng Tao Liang Hu Xiaoyan Wang Yanjing Yang Yang Xu Wentao Liu A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages Frontiers in Immunology rosacea carvedilol macrophage TLR2 KLK5 cathelicidin |
| title | A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages |
| title_full | A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages |
| title_fullStr | A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages |
| title_full_unstemmed | A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages |
| title_short | A Novel Mechanism of Carvedilol Efficacy for Rosacea Treatment: Toll-Like Receptor 2 Inhibition in Macrophages |
| title_sort | novel mechanism of carvedilol efficacy for rosacea treatment toll like receptor 2 inhibition in macrophages |
| topic | rosacea carvedilol macrophage TLR2 KLK5 cathelicidin |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.609615/full |
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