STING-dependent microglial inhibition by irisin ameliorates neuroinflammation in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS), characterized by microglial activation and polarization as key drivers of disease pathogenesis. Irisin, an exercise-induced myokine, has been reported to exhibit neuroprotective effects, including anti-inflammatory activity and cognitive improvement. To investigate the therapeutic potential of irisin in the experimental autoimmune encephalomyelitis (EAE) mouse model and its effects on microglial behavior along with the underlying molecular mechanisms, we conducted the present study. Results demonstrated that irisin treatment significantly alleviated EAE severity, evidenced by reduced disease incidence, attenuated weight loss, and improved neurological scores. Histopathological analysis revealed that irisin suppressed inflammatory cell infiltration and reduced demyelination in spinal cord tissues. Furthermore, irisin inhibited microglial overactivation and promoted a phenotypic shift from the pro-inflammatory M1 to the anti-inflammatory M2 microglia. Mechanistically, immunofluorescence co-localization and Western blot analyses confirmed that these beneficial effects were mediated via suppression of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, as indicated by downregulation of STING and phosphorylated interferon regulatory factor 3 (p-IRF3) expression. Collectively, these findings indicate that irisin alleviates neuroinflammation and exerts neuroprotective effects in EAE by modulating microglial activity through inhibition of the cGAS-STING pathway, underscoring its potential as a novel therapeutic candidate for MS.