Multi-tier signaling and epigenomic reprogramming orchestrate microglial inflammatory states and functions associated with demyelination

The extensive heterogeneity of microglia inflammatory states accompanying neurodegenerative diseases underscores the complex molecular mechanisms that regulate these cells. Here, we report on transcriptional effectors that control microglial inflammatory polarization associated with brain demyelination in mice. Using flow cytometry, microscopy and RNA-seq, we identified two dominant, functionally distinct states of Clec7a+CD229+ inflammatory microglia, discriminated from one another by CD11c expression. Epigenomic analyses implicated genome-wide nucleosome remodeling to the polarization process, driven by state-associated stimulation of transcription factors that included Pu.1, AP-1, Bhlhe40 and Egr2, as well as re-calibration of homeostatic input provided by Mef2. Loss-of-function experiments validated the physiological relevance of Trem2, Mef2a and Egr2 to the microglial inflammatory polarization process in the demyelinating brain. Therefore, distinct configurations of signaling input cooperate with epigenetic mechanisms to reprogram the transcriptional output of microglia to enable their inflammatory functions.