Interferon regulatory factor 8/interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia

Background: recent fate-mapping studies establish that microglia,the resident mononuclear phagocytes of the cns,are distinct in origin from the bone marrow-derived myeloid lineage. interferon regulatory factor 8 (irf8,also known as interferon consensus sequence binding protein) plays essential roles in development and function of the bone marrow-derived myeloid lineage. however,little is known about its roles in microglia.methods: the cns tissues of irf8-deficient mice were immunohistochemically analyzed. pure microglia isolated from wild-type and irf8-deficient mice were studied in vitro by proliferation,immunocytochemical and phagocytosis assays. microglial response in vivo was compared between wild-type and irf8-deficient mice in the cuprizon-induced demyelination model.results: our analysis of irf8-deficient mice revealed that,in contrast to compromised development of irf8-deficient bone marrow myeloid lineage cells,development and colonization of microglia are not obviously affected by loss of irf8. however,irf8-deficient microglia demonstrate several defective phenotypes. in vivo,irf8-deficient microglia have fewer elaborated processes with reduced expression of iba1/aif1 compared with wild-type microglia,suggesting a defective phenotype. irf8-deficient microglia are significantly less proliferative in mixed glial cultures than wild-type microglia. unlike irf8-deficient bone marrow myeloid progenitors,exogenous macrophage colony stimulating factor (colony stimulating factor 1) (m-csf (csf1)) restores their proliferation in mixed glial cultures. in addition,irf8-deficient microglia exhibit an exaggerated growth response to exogenous granulocyte-macrophage colony stimulating factor (colony stimulating factor 2) (gm-csf (csf2)) in the presence of other glial cells. irf8-deficient microglia also demonstrate altered cytokine expressions in response to interferon-gamma and lipopolysaccharide in vitro. moreover,the maximum phagocytic capacity of irf8-deficient microglia is reduced,although their engulfment of zymosan particles is not overtly impaired. defective scavenging activity of irf8-deficient microglia was further confirmed in vivo in the cuprizone-induced demyelination model in mice.conclusions: this study is the first to demonstrate the essential contribution of irf8-mediated transcription to a broad range of microglial phenotype. microglia are distinct from the bone marrow myeloid lineage with respect to their dependence on irf8-mediated transcription. © 2012 horiuchi et al.; licensee biomed central ltd.