title: GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling.
abstract: M-CSF and GM-CSF are mediators involved in regulating the numbers and function of macrophage lineage populations and have been shown to contribute to macrophage heterogeneity. Type I IFN is an important mediator produced by macrophages and can have profound regulatory effects on their properties. In this study, we compared bone marrow-derived macrophages (BMM) and GM-CSF-induced BMM (GM-BMM) from wild-type and IFNAR1(-/-) mice to assess the contribution of endogenous type I IFN to the phenotypic differences between BMM and GM-BMM. BMM were capable of higher constitutive IFN-beta production, which contributed significantly to their basal transcriptome. Microarray analysis found that of the endogenous type I IFN-regulated genes specific to either BMM or GM-BMM, 488 of these gene alterations were unique to BMM, while only 50 were unique to GM-BMM. Moreover, BMM displayed enhanced basal mRNA levels, relative to GM-BMM, of a number of genes identified as being dependent on type I IFN signaling, including Stat1, Stat2, Irf7, Ccl5, Ccl12, and Cxcl10. As a result of prior type I IFN "priming," upon LPS stimulation BMM displayed increased activation of the MyD88-independent IRF-3/STAT1 pathways compared with GM-BMM, which correlated with the distinct cytokine/chemokine profiles of the two macrophage subsets. Furthermore, the autocrine type I IFN signaling loop regulated the production of the M1 and M2 signature cytokines, IL-12p70 and IL-10. Collectively, these findings demonstrate that constitutive and LPS-induced type I IFN play significant roles in regulating the differences in phenotype and function between BMM and GM-BMM.
authors.affiliation: Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fleetwood
authors.forename: Hang
authors.initials: H
authors.lastname: Dinh
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cook
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000276:immunology; D019070:Cell Lineage; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D050838:Interferon Regulatory Factor-3 / Q000187:drug effects / Q000378:metabolism; D007370:Interferon Type I / Q000187:drug effects* / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D019707:Receptors, Chemokine / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
chemical_list: D016207:Cytokines; C508032:Ifnar1 protein, mouse; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D014157:Transcription Factors; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor