194: IRF8 regulates autophagy and activates microglia to exacerbate neuroinflammation

IRF8 is a transcription factor of the IRF family expressed in macrophages and dendritic cells (DCs). It enhances type I interferon induction in pDCs and IL12p40 in CD8 + DCs and macrophages. We have observed that IRF8 regulates transcription of a series of genes in the autophagy pathway in macrophages and DCs in response to IFNg and toll-like receptor signaling, and plays a critical role in the formation of autophagosomes and their fusion with lysosomes. Recently, IRF8 was identified as a risk factor for several autoimmune diseases including multiple sclerosis (MS) in SNP based epidemiological studies. MS is a neuroinflammatory disease that involves activation and expansion of Th17, Th1 T cells as well as microglia, the antigen presenting cells of the central nervous system. Since the SNPs for MS lie in the 3′ noncoding regions of IRF8 , regulated expression of IRF8 likely accounts for its role in MS neuroinflammation. Because the mechanism by which IRF8 contributes to MS pathogenesis has not been clarified, we have undertaken in depth analysis of IRF8 activity in the mouse model of MS. Our results indicate that IRF8 plays a critical role at multiple steps of the disease, from the onset to progression in the periphery and the CNS, including activation and expansion of microglia during neuroinflammation. These observations are discussed in the context of its role in regulating autophagy.