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Transcriptional regulation of homeostatic and disease-associated-microglial genes by IRF1, LXR?, and CEBP?.

ABSTRACT: Microglia transform from homeostatic to disease-associated-microglia (DAM) profiles in neurodegeneration. Within DAM, we recently identified distinct pro-inflammatory and anti-inflammatory sub-profiles although transcriptional regulators of homeostatic and distinct DAM profiles remain unclear. Informed by these studies, we nominated CEBP?, IRF1, and LXR? as likely regulators of homeostatic, pro-inflammatory and anti-inflammatory DAM states and performed in-vitro siRNA studies in primary microglia to identify roles of each transcriptional factor (TF) in regulating microglial activation, using an integrated transcriptomics, bioinformatics and experimental validation approach. Efficient (>70%) silencing of TFs in microglia revealed reciprocal regulation between each TF specifically following pro-inflammatory activation. Neuroinflammatory transcriptomic profiling of microglia coupled with qPCR validation revealed distinct gene clusters with unique patterns of regulation by each TF, which were independent of LPS stimulation. While all three TFs (especially IRF1 and LXR?) positively regulated core DAM genes (Apoe, Axl, Clec7a, Tyrobp, and Trem2) as well as homeostatic and pro-inflammatory DAM genes, LPS, and IFN? increased pro-inflammatory DAM but suppressed homeostatic and anti-inflammatory DAM gene expression via an Erk1/2-dependent signaling pathway. IRF1 and LXR? silencing suppressed microglial phagocytic activity for polystyrene microspheres as well as fA?42 while IRF1 silencing strongly suppressed production of pro-inflammatory cytokines in response to LPS. Our studies reveal complex transcriptional regulation of homeostatic and DAM profiles whereby IRF1, LXR?, and CEBP? positively regulate both pro- and anti-inflammatory DAM genes while activating stimuli independently augment pro-inflammatory DAM responses and suppress homeostatic and anti-inflammatory responses via Erk signaling. This framework can guide development of therapeutic immuno-modulatory strategies for neurodegeneration.

SUBMITTER: Gao T

PROVIDER: S-EPMC7190149 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Transcriptional regulation of homeostatic and disease-associated-microglial genes by IRF1, LXRβ, and CEBPα.

Gao Tianwen T Jernigan Janna J Raza Syed Ali SA Dammer Eric B EB Xiao Hailian H Seyfried Nicholas T NT Levey Allan I AI Rangaraju Srikant S

Glia 20190713 10

Microglia transform from homeostatic to disease-associated-microglia (DAM) profiles in neurodegeneration. Within DAM, we recently identified distinct pro-inflammatory and anti-inflammatory sub-profiles although transcriptional regulators of homeostatic and distinct DAM profiles remain unclear. Informed by these studies, we nominated CEBPα, IRF1, and LXRβ as likely regulators of homeostatic, pro-inflammatory and anti-inflammatory DAM states and performed in-vitro siRNA studies in primary microgli ...[more]

PMID: 31301160

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Project description:Microglia, the brain-resident myeloid cells, are strongly implicated in Alzheimer's disease (AD) pathogenesis by human genetics. However, the mechanisms by which microglial gene expression is regulated in a region-specific manner over the course of normal aging and in neurodegenerative disease are only beginning to be deciphered. Herein, we used a specific marker of microglia (TMEM119) and a cell-type expression profiling tool (CellMapper) to identify a human microglial gene expression module. Surprisingly, we found that microglial module genes are robustly expressed in several healthy human brain regions known to be vulnerable in AD, in addition to other regions affected only later in disease or spared in AD. Surveying the microglial gene set for differential expression over the lifespan in mouse models of AD and a related tauopathy revealed that the majority of microglial module genes were significantly upregulated in cortex and hippocampus as a function of age and transgene status. Extending these results, we also observed significant upregulation of microglial module genes in several AD-affected brain regions in addition to other regions using postmortem brain tissue from human AD samples. In pathologically confirmed AD cases, we found preliminary evidence that microglial genes may be dysregulated in a sex-specific manner. Finally, we identified specific and significant overlap between the described microglial gene set-identified by unbiased co-expression analysis-and genes known to impart risk for AD. Our findings suggest that microglial genes show enriched expression in AD-vulnerable brain regions, are upregulated during aging and neurodegeneration in mice, and are upregulated in pathologically affected brain regions in AD. Taken together, our data-driven findings from multiple publicly accessible datasets reemphasize the importance of microglial gene expression alterations in AD and, more importantly, suggest that regional and sex-specific variation in microglial gene expression may be implicated in risk for and progression of neurodegenerative disease.

Dataset Information

Transcriptional regulation of homeostatic and disease-associated-microglial genes by IRF1, LXR?, and CEBP?.

Publications

Transcriptional regulation of homeostatic and disease-associated-microglial genes by IRF1, LXRβ, and CEBPα.

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