REV-ERB agonist suppresses IL-17 production in γδT cells and improves psoriatic dermatitis in a mouse model

• Published in: Biomedicine & pharmacotherapy Vol. 144; p. 112283
• Main Authors: Wang, Shangyi, Kozai, Mina, Mita, Hironobu, Cai, Zimeng, Masum, Md. Abdul, Ichii, Osamu, Takada, Kensuke, Inaba, Mutsumi
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-12-2021; Elsevier
• Subjects: Administration, Cutaneous; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Cells, Cultured; Disease Models, Animal; Down-Regulation; Female; IL-17; Interleukin-17 - metabolism; Intraepithelial Lymphocytes - drug effects; Intraepithelial Lymphocytes - immunology; Intraepithelial Lymphocytes - metabolism; Mice; Mice, Knockout; Nuclear receptor; Nuclear Receptor Subfamily 1, Group D, Member 1 - agonists; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism; Psoriasis; Psoriasis - drug therapy; Psoriasis - immunology; Psoriasis - metabolism; Psoriasis - pathology; Pyrrolidines - administration & dosage; Pyrrolidines - pharmacology; REV-ERB; Signal Transduction; Skin - drug effects; Skin - immunology; Skin - metabolism; Thiophenes - administration & dosage; Thiophenes - pharmacology; γδT cells; Nuclear receptor; Psoriasis; REV-ERB; γδT cells; IL-17
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112283

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and cellular infiltration. Studies have shown that disease development depends on proinflammatory cytokines, such as interleukin (IL)-23 and IL-17. It has been suggested that IL-23 produced by innate immune cells, such as macrophages, stimulates a subset of helper T cells to release IL-17, promoting neutrophil recruitment and keratinocyte proliferation. However, recent studies have revealed the crucial role of γδT cells in psoriasis pathogenesis as the primary source of dermal IL-17. The nuclear receptors REV-ERBs are ligand-dependent transcription factors recognized as circadian rhythm regulators. REV-ERBs negatively regulate IL-17-producing helper T cells, whereas the involvement of REV-ERBs in regulating IL-17-producing γδT (γδT17) cells remains unclear. Here we revealed the regulatory mechanism involving γδT17 cells through REV-ERBs. γδT17 cell levels were remarkably elevated in the secondary lymphoid organs of mice that lacked an isoform of REV-ERBs. A synthetic REV-ERB agonist, SR9009, suppressed γδT17 cells in vitro and in vivo. Topical application of SR9009 to the skin reduced the inflammatory symptoms of psoriasiform dermatitis in mice. The results of this study provide a novel therapeutic approach for psoriasis targeting REV-ERBs in γδT17 cells.
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•IL-17 production by γδT cells is under the control of REV-ERBs.•Synthetic REV-ERB agonist SR9009 suppresses IL-17 production by γδT cells.•Topical application of SR9009 to the skin ameliorates psoriatic dermatitis in mice.•Targeting REV-ERBs in γδT cells can be a novel therapeutic approach for psoriasis.