Meningoencephalitis of unknown origin (MUO) encompasses a heterogeneous group of non-infectious, presumed autoimmune, central nervous system diseases in dogs and remains a major therapeutic challenge in veterinary neurology. Mounting evidence from both experimental and clinical studies has highlighted the pivotal role of T helper 17 (Th17) cells and their proinflammatory cytokines, especially interleukin-17A (IL-17A), in mediating neuroinflammation similar to that seen in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) models. REV-ERBs are nuclear receptors that act as transcriptional repressors and regulate immune responses, circadian rhythm, and metabolism. Synthetic REV-ERB agonists, such as SR9009, SR9011, and SR12418, have demonstrated selective suppression of Th17 differentiation and function, reduction of disease severity, and improved safety profiles in preclinical autoimmune models. In addition to Th17 differentiation, REV-ERB's role in other components of the immunomodulating system is ever-growing. Preclinical and translational data support the further exploration of REV-ERB agonists as a potential addition to the targeted immunomodulatory therapies for canine MUO. By continuing to investigate REV-ERB compounds as a component of MUO therapy, researchers can assess their potential for improved efficacy and reduce the side effects associated with traditional immunosuppressive regimens. This review integrates mechanistic insights from immunology, circadian biology, and experimental models, and outlines future directions for clinical translation, highlighting the relevance of REV-ERB agonists in advancing veterinary neuroimmunology and in informing comparative approaches to human neuroautoimmune disease.
