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• W3016021790 abstract "To the Editor: Alopecia areata (AA) is a common T-cell–mediated autoimmune disorder, and the exact pathomechanism remains elusive. Statins are hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors widely used around the world as lipid-lowering agents and to treat cardiovascular disease. Recently, there are human prospective observational, retrospective, and case series of the effectiveness of simvastatin treatment on AA.1Cervantes J. Jimenez J.J. DelCanto G.M. Tosti A. Treatment of alopecia areata with simvastatin/ezetimibe.J Investig Dermatol Symp Proc. 2018; 19: S25-S31Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,2Choi J.W. Suh D.W. Lew B.L. Sim W.Y. Simvastatin/ezetimibe therapy for recalcitrant alopecia areata: an open prospective study of 14 patients.Ann Dermatol. 2017; 29: 755-760Crossref PubMed Scopus (6) Google Scholar However, the exact mechanism by which statins improve AA is not yet known. Here, we investigate the putative therapeutic effect and mechanism of simvastatin in the treatment of AA through in vitro studies. To mimic the inflammatory responses in AA, we cotreated polyinosinic:polycytidylic acid [poly(I:C)] and interferon (IFN) γ to primary cultured human outer root sheath (ORS) cells.3Shin J.M. Choi D.K. Sohn K.C. et al.Induction of alopecia areata in C3H/HeJ mice using polyinosinic-polycytidylic acid (poly[I:C]) and interferon-gamma.Sci Rep. 2018; 8: 12518Crossref PubMed Scopus (5) Google Scholar First, we examined whether simvastatin affects inflammatory reactions in ORS cells. Cotreatment of poly(I:C) and IFN-γ increased the expression of inflammatory cytokines, including interleukin (IL) 6, IL-8, tumor necrosis factor (TNF) α, and IL-1β. Simvastatin pretreatment downregulated poly(I:C)- and IFN-γ–induced IL-6 and IL-8 messenger RNA (mRNA) levels and inhibited secretion of IL-6, IL-8, and TNF-α (Fig 1, A and B). Next, we checked the effect of simvastatin on the expression of IFN-inducible C-X-C motif chemokines (CXCL) 9-11 and major histocompatibility complex (MHC) I. However, simvastatin did not decrease IFN-γ–induced CXCL9-11 and MHC I expression (Fig 1, C and D). To investigate putative mechanisms, we examined the effect of simvastatin on the nuclear factor κB signaling pathway, which is a central regulator in inflammatory responses. Simvastatin significantly inhibited poly(I:C)- and IFN-γ–induced phosphorylation of p65 in a dose-dependent manner. Moreover, simvastatin decreased phosphorylation of signal transducer and activator of transcription (STAT) 3, which is another critical player linked to AA (Fig 1, E and F). Simvastatin also significantly inhibited poly(I:C)- and IFN-γ–induced reactive oxygen species (ROS) production in a dose-dependent manner (Fig 1, G). Finally, we determined whether simvastatin regulates Wnt/β-catenin signaling and hair growth. Simvastatin increased cell viability and TOPflash activity, indicating transcriptional activation of β-catenin (Fig 2, A and B). However, simvastatin did not affect other hair growth–related genes (Fig 2, C). Statins exert pleiotropic anti-inflammatory properties in vitro and in vivo. Previously, statins have been reported to modulate cytokine secretion and T-cell responses and to inhibit the secretion of proinflammatory cytokines.4Chow S.C. Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases.Arch Immunol Ther Exp. 2009; 57: 243-251Crossref PubMed Scopus (57) Google Scholar In this experiment, we showed that simvastatin directly attenuates inflammatory reactions in hair follicle cells, especially in ORS cells. However, simvastatin did not produce a significant effect on the expression of CXCL 9-11 and MHC class I. This indicates that simvastatin may not regulate IFN-γ–induced gene expression but that it can inhibit TNF-α–induced nuclear factor κB transcriptional activity in ORS cells, resulting in inflammatory response reduction in AA progression. One of the therapeutic mechanisms of simvastatin in AA is considered to be inhibition of the Janus kinase (JAK)/STAT signaling pathway. We additionally showed the effect of simvastatin on inhibition of the nuclear factor κB pathway, STAT3 pathway, and ROS production, which are closely related to the pathophysiology of AA. There are in vitro studies showing that statins modulate Wnt/β-catenin signaling in various cells.5Lin C.L. Cheng H. Tung C.W. et al.Simvastatin reverses high glucose-induced apoptosis of mesangial cells via modulation of Wnt signaling pathway.Am J Nephrol. 2008; 28: 290-297Crossref PubMed Scopus (36) Google Scholar Our results indicate that simvastatin could induce hair regrowth by activating Wnt/β-catenin signaling and exerting its anti-inflammatory effect simultaneously in patients with AA. In summary, we suggest that simvastatin improves AA through pleiotropic anti-inflammatory properties; inhibition of NF-κB, the JAK/STAT pathway, and ROS production; and activation of the Wnt/β-catenin signaling pathway." @default.
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• W3016021790 date "2021-03-01" @default.
• W3016021790 modified "2023-09-30" @default.
• W3016021790 title "Putative therapeutic mechanisms of simvastatin in the treatment of alopecia areata" @default.
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• W3016021790 doi "https://doi.org/10.1016/j.jaad.2020.03.102" @default.
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