FIGURE 10.

Tbk1 inhibition by Amlexanox modifiedy the microglial and immune response in cortical Stab Wound Injury (SWI) injury. (A) Blockade of Tbk1 alone by Amlexanox (AMX), in absence of additional damage, is sufficient to increase the expression of IL-17, CSF1, CSF1R, Flt3, Flt3R, and IL-13, indicating an initial baseline pro-inflammatory state; upon SWI injury, AMX administration causes the substantial expansion of reactive microglia with immunohistochemical and expression profile similar to the Disease-Associated Microglia described in neurodegenerative conditions as well as the significant increase in the infiltration by lymphocytes and monocytes/macrophages. The ultimate effect appears to be increased astrogliosis and extensive deposition of CSPG scar. (B) At least two molecular mechanisms are proposed for AMX effect on microglial phenotype: the de-repression of the RIPK1 pathway and the de-activation of the STING pathway. The concomitant upregulation of inflammatory cytokines, some of lymphocytic origin such as IL-17 and IFN-γ, is likely to contribute to the peculiar microglial phenotype.