Activation of the stimulator of interferon genes (STING) adaptor attenuates experimental autoimmune encephalitis (THER6P.848)

Abstract Activation of Stimulator of Interferon genes (STING) adaptor causes the release of IFN αβ in most of the cells, an activity that is tightly controlled to avoid continuous immune activation that could lead to autoimmunity. Here we show that STING activators can be used systemically to suppress experimental autoimmune encephalitis following myelin oligodendrocyte (MOG) immunization through STING-IFN αβ pathway. DNA nanoparticles (DNPs) attenuated MOG-specific effector responses in CNS and spleen. Therapeutic responses to DNPs are dependent on STING adaptor and IFN αβ receptors as they were abolished in mice lacking those genes. Additionally, indoleamine 2,3 dioxygenase enzyme (IDO) is crucial for therapeutic responses to DNPs as the loss of IDO1 gene in hematopoietic cells and IDO inhibition by 1-methyl-D-tryptophan had ablated those responses. Cyclic diguanylate monophosphate (c-diGMP), a direct STING activator also attenuated EAE progression and disease severity. Thus, Systemic administration of DNPs and c-diGMP can attenuate EAE through STING-IFN αβ-IDO regulatory pathway that is activated in certain immune cells subsets to overcome CNS specific autoimmunity. These findings emphasize a previously unappreciated role of STING activators to attenuate autoimmunity.