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-β 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. Footnotes Abbreviations: BMM=bone marrow-derived macrophages, GM-BMM=GM-CSF-derived macrophages, BMM=M-CSF-derived macrophages, DC=dendritic cell, TAM=tumor-associated macrophage, GO=gene ontology, FDR–false discovery rate, PCA=principal component analysis The online version of this paper, found at www.jleukbio.org includes supplemental information. Received November 17, 2008. Revision received March 11, 2009. Accepted March 31, 2009. Society for Leukocyte Biology
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GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on Type I interferon signaling
Fleetwood, Andrew J.; Dinh, Hang; Cook, Andrew D.; Hertzog, Paul J; Hamilton, John A.
Follow Journal of Leukocyte Biology
, Volume 86 (2): 411
Fed of American Socs for Experimental Biology – Aug 1, 2009
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