<p>Microglia and Th17 cells are the major immunopathogenic cells in multiple sclerosis and its animal model of immune aspects, experimental autoimmune encephalomyelitis (EAE). While studies have highlighted the distinct roles of microglia and Th17 cells in EAE, it remains unclear whether microglia, as potential professional antigen-presenting cells, activate and stabilize the effector program of EAE-pathogenic Th17 cells in vivo; and if so, whether the Th17 could in turn reinforce the active state of the microglia. Our data demonstrate in an array of mouse models, including active/passive-EAE and transgenic mice, a microglia-Th17 feed-forward activation loop drives EAE disease progression through a mechanism dependent on both MHC-II, proinflammatory cytokines, inflammatory chemokines as well as STING→NF-κB pathway in the microglia and effector cytokines produced by the pathogenic Th17 cells. We also captured and identified the molecular properties of the feed-forward loop, which are two-cell entities of microglia-Th17, and proved them as the functional units of antigen presentation and bi-directional activation between the two cell types. Moreover, ACT001, an orphan drug to treat glioblastoma, disrupts this feed-forward activation loop by inhibiting the STING→NF-κB pathway in microglia, thereby alleviating EAE. These findings emphasize the importance of interactions and bi-directional activations between microglia and Th17 in the autoimmune neuroinflammation, and provide rationale for further investigation on ACT001 as therapeutic option for autoimmune inflammatory diseases driven by similar mechanisms.</p>