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Journal of Neuroinflammation

, 9:227

First Online: 28 September 2012Received: 16 May 2012Accepted: 13 August 2012

Abstract

BackgroundRecent 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.

MethodsThe 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.

ResultsOur 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.

ConclusionsThis 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.

KeywordsMicroglia Interferon regulatory factor Phagocytosis Cytokine Cuprizone-induced demyelination AbbreviationsBMBone marrow

BMDMBM-derived microglia

BSABovine serum albumin

CSF1RColony stimulating factor 1 receptor

DAPI4,6-diamidio-2-phenylindole

DCDendritic cell

DMEMDulbecco’s modified Eagle’s medium

EdU5-ethynyl-2′-deoxyuridine

G-CSFGranulocyte colony stimulating factor

GM-CSFGranulocyte-macrophage colony stimulating factor

HBSSHanks’ balanced salt solution

ICSBPinterferon consensus sequence binding protein

IFNB1Interferon-β1

IL12BInterleukin-12b

IRFInterferon regulatory factor

LFBLuxol fast blue

LPSLipopolysaccharide

MACSMagnetic cell sorting

M-CSFMacrophage colony stimulating factor

MFIMean fluorescent intensity

MPMononuclear phagocyte

PASPeriodic acid Schiff

qPCRreal-time PCR.

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Author: Makoto Horiuchi - Kouji Wakayama - Aki Itoh - Kumi Kawai - David Pleasure - Keiko Ozato - Takayuki Itoh

Source: https://link.springer.com/







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