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Multi-tier signaling and epigenomic reprogramming drive microglial inflammatory states and functions associated with demyelination [RNA-seq]

ABSTRACT: 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 state 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 extensive 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. Notably, a H3K27me3-based epigenetic gatekeeping mechanisms controls transcription of Egr2 and Bhlhe40 genes. Loss-of-function experiments validated the physiological relevance of Trem2, Mef2a and Egr2 to the microglial inflammatory state polarization process in the demyelinating brain. Therefore, distinct configuration of transcriptional input cooperate with epigenetic mechanisms to specify microglial inflammatory states and functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE302857 | GEO | 2026/04/29

REPOSITORIES: GEO

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Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

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Multi-tier signaling and epigenomic reprogramming drive microglial inflammatory states and functions associated with demyelination [RNA-seq]

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