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Differential expression of IRF8 in subsets of macrophages and dendritic cells and effects of IRF8 deficiency on splenic B cell and macrophage compartments.

ABSTRACT: IRF8, a transcription factor restricted primarily to hematopoietic cells, is known to influence the differentiation and function of dendritic cells (DC), macrophages, granulocytes and B cells. In human tonsil, IRF8 is expressed at high levels by intrafollicular macrophages and DC, but at much lower levels by tingible body macrophages in germinal centers (GCs) and little, if at all, by follicular DC. Spleens of IRF8-deficient mice had reduced numbers of white pulp follicles and GCs that were irregular in shape. The frequency of follicular B cells was significantly reduced while the population of marginal zone (MZ) B cells was increased. In addition, MZ macrophages were reduced in number and abnormally distributed, while metallophilic macrophages were normal. These findings demonstrate differential requirements for IRF8 among distinct subsets of B cells, DC, and macrophages.

SUBMITTER: Qi CF

PROVIDER: S-EPMC2745513 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Differential expression of IRF8 in subsets of macrophages and dendritic cells and effects of IRF8 deficiency on splenic B cell and macrophage compartments.

Qi Chen-Feng CF Li Zhaoyang Z Raffeld Mark M Wang Hongsheng H Kovalchuk Alexander L AL Morse Herbert C HC

Immunologic research 20090101 1

IRF8, a transcription factor restricted primarily to hematopoietic cells, is known to influence the differentiation and function of dendritic cells (DC), macrophages, granulocytes and B cells. In human tonsil, IRF8 is expressed at high levels by intrafollicular macrophages and DC, but at much lower levels by tingible body macrophages in germinal centers (GCs) and little, if at all, by follicular DC. Spleens of IRF8-deficient mice had reduced numbers of white pulp follicles and GCs that were irre ...[more]

PMID: 18663414

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Project description:ObjectivePeripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients exhibit a gene expression program (interferon [IFN] signature) that is attributed to overproduction of type I IFNs by plasmacytoid dendritic cells. Type I IFNs have been thought to play a role in the pathogenesis of SLE. This study was undertaken to examine an unexpected influence of monocyte/macrophages on the IFN signature.MethodsProinflammatory (classic) and antiinflammatory (nonclassic) monocyte/macrophages were sorted from mice and analyzed by RNA sequencing and quantitative polymerase chain reaction (qPCR). Type I IFN-?/?/? receptor (IFNAR-1) expression was determined by qPCR and flow cytometry. Macrophages were stimulated in vitro with IFN?, and pSTAT1was measured.ResultsTranscriptional profiling of peritoneal macrophages from mice with pristane-induced SLE unexpectedly indicated a strong IFN signature in classic, but not nonclassic, monocyte/macrophages exposed to the same type I IFN concentrations. Ifnar1 messenger RNA and IFNAR surface staining were higher in classic monocyte/macrophages versus nonclassic monocyte/macrophages (P < 0.0001 and P < 0.05, respectively, by Student's t-test). Nonclassic monocyte/macrophages were also relatively insensitive to IFN?-driven STAT1 phosphorylation. Humans exhibited a similar pattern: higher IFNAR expression (P < 0.0001 by Student's t-test) and IFN?-stimulated gene expression (P < 0.01 by paired Wilcoxon's rank sum test) in classic monocyte/macrophages and lower levels in nonclassic monocyte/macrophages.ConclusionThis study revealed that the relative abundance of different monocyte/macrophage subsets helps determine the magnitude of the IFN signature. Responsiveness to IFN? signaling reflects differences in IFNAR expression in classic (high IFNAR) compared to nonclassic (low IFNAR) monocyte/macrophages. Thus, the IFN signature depends on both type I IFN production and the responsiveness of monocyte/macrophages to IFNAR signaling.

Dataset Information

Differential expression of IRF8 in subsets of macrophages and dendritic cells and effects of IRF8 deficiency on splenic B cell and macrophage compartments.

Publications

Differential expression of IRF8 in subsets of macrophages and dendritic cells and effects of IRF8 deficiency on splenic B cell and macrophage compartments.

Similar Datasets

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