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

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.

ROR agonist hampers the proliferation and survival of postactivated CD8+ T cells through the downregulation of cholesterol synthesis-related genes.

Cholesterol is a major component of the lipid bilayers of cellular membranes. The synthesis of cholesterol is acutely elevated during T-cell activation to support T-cell growth and proliferation. There is a limited understanding of cholesterol metabolism reprogramming during T-cell activation. Retinoic acid receptor-related orphan receptors (RORs) are ligand-activated nuclear receptors that regulate the transcription of target genes. In this study, we demonstrated that the activation of RORs by a synthetic agonist (SR1078) impairs the proliferation and survival of postactivated CD8+ T cells. The inhibitory effects of SR1078 on CD8+ T-cell proliferation and survival were attributed to cholesterol depletion and downregulated expression of cholesterol metabolism-related genes. The overexpression of RORα or RORγt promoted apoptosis in the postactivated CD8+ T cells in vitro. The expression of RORα (but not that of RORγt) was markedly upregulated in the CD8+ T cells upon stimulation with an antigen in vivo. The functional deficiency of RORα enhanced CD8+ T-cell expansion during the response to bacterial infection. These results suggest that RORs are involved in the regulation of CD8+ T-cell-mediated immune response through the regulation of cholesterol metabolism, which can be modulated by a synthetic ROR agonist. The findings of this study can aid in the development of immunotherapeutic methods that target nuclear receptors.