MerTK triggered TGFB1 Autocrine Signal Controls Microglial Response to Neurodegeneration

Microglial phagocytosis has essential roles in neurodegeneration, but how phagocytotic processes may reciprocally regulate microglia remains to be better understood. Here, we show that microglial responses in the mouse model of pathological axonal degeneration depend on the phagocytic receptor MerTK. The MerTK-triggered downstream phospholipase-C signal is sufficient to induce the up-regulation of PU.1 and IRF8, the two central transcription factors governing microglial functions. Chromatin immunoprecipitation-sequencing analyses then identify that PU.1 and IRF8 directly target the gene locus of TGFB1, and disruption of this PU.1-IRF8 targeting site abolishes the induction of microglial TGFB1 during neurodegeneration. Of importance, such neurodegeneration-induced TGFB1 acts in an autocrine manner, with the microglia-specific deletion of TGFB1 or the receptors TGFBR1 or TGFBR2 blocking microglial responses. Moreover, microglial TGFB1 autocrine signal similarly occurs in the 5xFAD mouse model of Alzheimer's disease or human patients. These results have delineated a molecular mechanism designating microglial responses to neurodegeneration.