Blocking the IFN-gamma signal in the choroid plexus confers resistance to experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration and demyelination in the central nervous system (CNS). IFN-gamma (IFN-gamma), a critically important immunomodulator, has been widely studied in MS pathology. The confusing and complex effects of IFN-gamma in MS patients and rodent models, however, cause us to look more closely at its exact role in MS. In this study, we identified the role of the IFN-gamma signaling in the choroid plexus (CP) in the experimental autoimmune encephalomyelitis (EAE) model. We found that the IFN-gamma signal was rapidly amplified when CNS immune cell infiltration occurred in the CP during the progressive stage. Furthermore, using two CP-specific knockdown strategies, we demonstrated that blocking the IFN-gamma signal via knockdown of IFN-gamma R1 in the CP could protect mice against EAE pathology, as evidenced by improvements in clinical scores and infiltration. Notably, knocking down IFN-gamma R1 in the CP reduced the local expression of adhesion molecules and chemokines. This finding suggests that IFN-gamma signaling in the CP may participate in the pathological process of EAE by preventing pathological T helper (Th) 17(+) cells from infiltrating into the CNS. Finally, we showed that the unbalanced state of IFN-gamma signaling between peripheral lymphocytes and the choroid plexus may determine whether IFN-gamma has a protective or aggravating effect on EAE pathology. Above all, we discovered that IFN-gamma R1-mediated IFN-gamma signaling in the CP was a vital pathway in the pathological process of EAE.

Automated summary

This study identified the critical role of IFN-gamma signaling in the choroid plexus (CP) in the pathological process of experimental autoimmune encephalomyelitis (EAE). Blocking the IFN-gamma signal by knocking down IFN-gamma R1 in the CP protected mice against EAE pathology, as evidenced by improvements in clinical scores and infiltration. The study also revealed that IFN-gamma signaling in the CP may participate in the pathological process of EAE by preventing pathological Th17+ cells from infiltrating into the CNS.