Immuno-Responsive Gene-1: A mitochondrial gene regulates pathogenic Th17 in CNS autoimmunity mouse model

Pathogenic Th17 cells are crucial to CNS autoimmune diseases like multiple sclerosis (MS), though their control by endogenous mechanisms is unknown. RNAseq analysis of brain glial cells identified immuno-responsive gene 1 (Irg1), a mitochondrial-related enzyme-coding gene, as one of the highly upregulated gene under inflammatory conditions which were further validated in the spinal cord of animals with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Moreover, Irg1 mRNA and protein levels in myeloid, CD4, and B cells were higher in the EAE group, raising questions about its function in CNS autoimmunity. We observed that Irg1 knockout (KO) mice exhibited severe EAE disease and greater mononuclear cell infiltration, including triple-positive CD4 cells expressing IL17a, GM-CSF, and IFNγ. Lack of Irg1 in macrophages led to higher levels of Class II expression and polarized myelin primed CD4 cells into pathogenic Th17 cells through the NLRP3/IL1β axis. Our findings show that Irg1 in macrophages plays an important role in the formation of pathogenic Th17 cells, emphasizing its potential as a therapy for autoimmune diseases, including MS.