SIRT1 downregulation provokes immune-inflammatory responses in hair follicle outer root sheath cells and may contribute to development of alopecia areata

Background: Silent information regulator 1 (SIRT1), a type III histone deacetylase, is involved in various cuta-neous and systemic autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. However, little is known about the role of SIRT1 in the development of alopecia areata (AA). Objectives: This study investigated whether SIRT1 regulates the hair follicle immune system and is involved in AA pathogenesis. Methods: SIRT1 expression in human scalp tissue was analyzed using immunohistochemical staining, qPCR, and western blotting. The regulatory effect of SIRT1 was evaluated after stimulation with the double-stranded RNA mimic polyinosinic:polycytidylic acid (poly I:C) in hair follicle outer root sheath (ORS) cells and C3H/HeJ mice.Results: SIRT1 expression was significantly reduced in the AA scalp compared to the normal scalp. SIRT1 inhibition upregulated MHC class I polypeptide-related sequence A and UL16 binding protein 3 in hair follicle ORS cells. SIRT1 inhibition also promoted the production of Th1 cytokines (IFN-& gamma; and TNF-& alpha;), IFN-inducible chemokines (CXCL9 and CXCL10), and T cell migration in ORS cells. Conversely, SIRT1 activation suppressed the autoreactive inflammatory responses. The counteractive effect of the immune response by SIRT1 was mediated through the deacetylation of NF-& kappa;B and phosphorylation of STAT3.Conclusion: SIRT1 downregulation induces immune-inflammatory responses in hair follicle ORS cells and may contribute to AA development.& COPY; 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.