Multiple sclerosis (MS) is an autoimmune disease characterised by demyelination and inflammation of the central nervous system (CNS). While IFN-β is used as a first line treatment for slowing disease progression, and reducing relapse rate and CNS lesions in MS, its beneficial effects are often limited by neurological side effects and insufficient immune responses.
The mechanisms of action of IFN-β can be attributed to its signalling pathway in which signal transducers and activators of transcription 1 (STAT1) is a key transcription factor. Activity of STAT1 is regulated by phosphorylation of tyrosine 701 (pY-STAT1), which is essential for STAT1 activation, and serine 727 (pS-STAT1), whose function is poorly understood but is thought to play a role in maximising transcriptional activity.
In patients with active MS, pS-STAT1 levels have been found to be low in blood mononuclear cells and have been linked to low expression of a number of IFN-regulated genes compared to controls following IFN-β treatment1. By investigating further the role of pS-STAT1 in the CNS, the present study demonstrated that pS-STAT1 is protective against severe experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Interestingly, the clinical disease observed in the absence of pS-STAT1 was comparable to that observed in mice which lack complete STAT1, indicating that the severe EAE previously reported in STAT1-deficient mice2 may be a consequence of deficient pS-STAT1. This more severe disease in the absence of pS-STAT1 was accompanied by increased inflammatory lesions in the brain and spinal cord and differences in the expression of various cytokines and chemokines. This supports a regulatory role of pS-STAT1 in the IFN response in the CNS. Furthermore, the protective effects of pS-STAT1 during neuroinflammation suggest that it may be a promising target in advancing current understandings of the pathogenesis of MS.