IFN-γ signaling in astrocytes and microglia has opposite roles in CNS autoimmunity (P5170)

Abstract

Abstract IFN-γ, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Thus far, the role of IFN-γ in EAE has been largely studied through its effects on immune cells, while much less is known about its effects on central nervous system (CNS) cells, especially in vivo. In this study we for the first time dissected the in vivo effects and mechanisms of IFN-γ signaling in astrocytes and microglia and found that IFN-γ signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-γ signaling in astrocytes ameliorated EAE, while in microglia it increased disease severity. Silencing IFN-γ signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, while blocking IFN-γ signaling in microglia increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-γ signaling in astrocytes ameliorated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-γ signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-γ in EAE pathogenesis, and also highlights an opportunity for development of MS therapies directed at CNS cells.