Interferon regulatory factor 8 deficiency causes phenotypic and functional changes in myeloid cells inside and outside the CNS (P4145)

Abstract

Abstract We identified IRF8 as a constitutive and IFN-γ-stimulated nuclear factor in microglia of the CNS. IRF8 is a transcription factor with a key role in the cellular response to IFN-γ but is also pivotal in myeloid cell differentiation. Here we employed IRF8 KO mice to determine the role of IRF8 in microglial development and function in the healthy CNS and in the microglial response to injury (facial nerve axotomy [FNA]) or infection (West Nile Virus [WNV] encephalitis). Microglia were present in the CNS of IRF8 KO mice but showed altered morphology and significantly reduced surface area and had alterations in a number of key markers including reduced levels of Iba1, CCR2 and CCR5 but increased levels tomato lectin binding. Following FNA the microglial response was markedly delayed and attenuated in IRF8 KO mice and the wrapping of motor neuron cell bodies by microglia involved in synaptic stripping and phagocytosis was incomplete. Finally, IRF8 KO mice had increased susceptibility to WNV accompanied by a marked reduction in both microglial cell activation and leukocyte accumulation in the brain. In the periphery, ly6Cint monocytes were increased in number but exhibited defective trafficking to the infected CNS while ly6Chi monocytes were almost completely absent. In conclusion: (1) IRF8 is a major intrinsic determinant of the microglial phenotype in the healthy and the diseased CNS, and (2) IRF8 has a crucial role in the development and trafficking of inflammatory monocytes.