1 IRF8 binds specific DNA motifs and shapes myeloid cell identity and inflammation. To study mechanisms by which IRF8 shapes myeloid cell identity and initiates innate immune responses, we examined, by ChIP-seq analysis, global IRF8 binding on progenitor cells and bone marrow derived macrophages with and without stimulation by LPS (ligand for TLR4). We found that in all cases IRF8 binds numerous sites in the genome, many of which coincides with two distinct DNA motifs, ISRE and ETS/IRF composite sites, the consensus being GAAAnnnGAAA/T and GAAnnnGAAA, respectively. IRF8 binding was strongly increased when cells were stimulated by LPS. The ISRE sites were likely occupied by IRF dimers, while the composite sites are bound by a heterodimer of SPI1/IRF8 or IRF8/SPI1 (PU.1). It is interesting that IRF8 binding was often found relatively far away from the target genes, suggesting that IRF8, together with other factors, forms large enhancers, and provides sustained transcription of select genes, furnishing cell type identity and robust inflammatory responses. Together, IRF8 shapes overall transcriptome profiles of macrophages in quiescence and after stimulation, This idea is consistent with our ATAC-seq data showing that DNA accessibility patterns are extensively altered when the Irf8 gene is deleted from macrophages. 2 IRF8 controls microglia transcriptomes and affects neuroinflammation. Recently, we began studying IRF8 in microglia and its role in neuroinflammation. Microglia, central to innate munity in the brain have many additional roles, including clearance of wastes. Microglia also influence neuron synapse formation and the maintenance of blood vessels in he brain. IRF8 and SPI1 (PU.1) play a central role in early microglia development in the embryonic stage. In adult brain, IRF8 KO microglia, although present in normal numbers, are abnormal in appearance; they have few cytoplasmic extensions, suggestive of activated microglia. Microglia specific surface markers, such as Iba1 and Cx3cr1 are present but lower in expression levels. RNA-seq data revealed that IRF8 KO microglia are deficient in many genes that define microglia, such as P2ry12, Sall I, Sparc and Pilra/b. Moreover, IRF8 KO microglia expressed many so called disease-associated microglia (DAM) genes found in Alzheimers disease (AD) and its mouse models, including Apoe, Cst1, Cst7. Some of DAM genes are risk factors for Alzheimers disease. Another unusual feature of IRF8 KO microglia is the expression of some interferon stimulated genes (ISG), including Irf4 and Irf7, indicating inflammatory conditions. Thus IRF8 broadly controls microglia gene expression programs and influences microglias many functions. IRF8 appears to have dual roles in neuroinflammation and affects the course of neurodegenerative diseases both positively and negatively. Further analysis of the role of IRF8 would shed light on the mechanism of neuroinflammation.

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