IRF8 is induced by IFN gamma and pathogen recognition receptor engagement and plays an essential role in the elimination of various pathogens and promotion of inflammatory responses. Recent epidemiological studies have reported that IRF8 is a risk factor for certain autoimmune diseases, including multiple sclerosis (MS) and systemic lupus erythematosus (SLE). TGF-beta signaling is thought to play an important role in the onset of MS, and the disease progression is associated with the presence of proinflammatory cytokines However, etiology of the disease has not been fully understood. To elucidate a molecular basis of the linkage between IRF8 and MS, we investigated a mouse model of MS, experimental allergic encephalomyelitis (EAE). We showed that Irf8-/- mice do not develop EAE following antigen challenge and do not suffer from characteristic limb paralysis. Accordingly, Irf8-/- mice failed to produce MS-signature cytokines IL17 and IFN gamma, produced by inflammatory T cells. The subsequent analyses with Irf8 conditional knockout mice that lack IRF8 in macrophages or T cells found that IRF8 acting in macrophages and DCs is primarily responsible for the disease, and IRF8 in T cells is not. It has been recently shown that a specific integrin molecule,AlphaVBeta8 expressed on macrophages and DCs is required for activating latent TGFβthat then transmits TGFbeta signaling to naive T cells. We demonstrated that IRF8 stimulates AlphaVBeta8 ranscription in macrophages and DCs, and facilitates activation of inflammatory T cells. Additional experiments showed that IRF8 also promotes other inflammatory pathways by stimulating the cytokine, IL23 and activating microglia in the central nervous system. Together, our study provides mechanistic insight on how IRF8 acts as a risk factor for NS and how it exacerbates neuroinflammation. Autophagy involves a long process that is activated by various stress. It is typically characterized by LC3 protein lipidation followed by autophagosome formation, which leads to the fusion with lysosomes and protein degradation. Each of the above processes is controlled by autophagy specific genes conserved from yeast to humans. Our initial microarray and ChIP-on chip analyses indicated that some of autophagy related genes are downregulated in Irf8-/- DCs relative to IRF8+/+ DCs. The follow-up study confirmed that IRF8 is required for expression of a large number of autophagy specific genes in both macrophages and DCs. Some of these genes are induced by IFN and Toll like receptor ligands. We found that IRF8 binds to the upstream promoter regions of a number of autophagy genes. Consistent with these findings, Irf8 -/- macrophages were defective in LC3 lipidation and autophagosome formation. These results indicate that IRF8 utilizes autophagy to eliminate certain pathogens including TB.

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U.S. National Inst/Child Hlth/Human Dev
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Haque, Nazmul; Ouda, Ryota; Chen, Chao et al. (2018) ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nat Commun 9:1145
Kurotaki, Daisuke; Nakabayashi, Jun; Nishiyama, Akira et al. (2018) Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors. Cell Rep 22:2628-2641
Kamada, Rui; Yang, Wenjing; Zhang, Yubo et al. (2018) Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc Natl Acad Sci U S A 115:E9162-E9171
Kamiyama, Reikou; Yoshimi, Ryusuke; Takeno, Mitsuhiro et al. (2018) Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus. Mod Rheumatol :1-11
Wang, Joshua W; Wu, Wai Hong; Huang, Tsui-Chin et al. (2018) Roles of Fc Domain and Exudation in L2 Antibody-Mediated Protection against Human Papillomavirus. J Virol 92:
Cougnoux, Antony; Drummond, Rebecca A; Collar, Amanda L et al. (2018) Microglia activation in Niemann-Pick disease, type C1 is amendable to therapeutic intervention. Hum Mol Genet 27:2076-2089
Valanparambil, Rajesh M; Tam, Mifong; Gros, Pierre-Paul et al. (2017) IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection. PLoS Pathog 13:e1006647
White, Christine L; Kessler, Patricia M; Dickerman, Benjamin K et al. (2016) Interferon Regulatory Factor 8 (IRF8) Impairs Induction of Interferon Induced with Tetratricopeptide Repeat Motif (IFIT) Gene Family Members. J Biol Chem 291:13535-45
Pan, Ji-An; Sun, Yu; Jiang, Ya-Ping et al. (2016) TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Mol Cell 61:720-733
Paschall, Amy V; Zhang, Ruihua; Qi, Chen-Feng et al. (2015) IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. J Immunol 194:2369-79

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