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Originally published online as doi:10.1189/jlb.1108702 on April 30, 2009

Published online before print April 30, 2009
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(Journal of Leukocyte Biology. 2009;86:411-421.)
© 2009 Society for Leukocyte Biology

GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on Type I interferon signaling

Andrew J. Fleetwood*, Hang Dinh*, Andrew D. Cook*, Paul J Hertzog*,{dagger} and John A. Hamilton*,1

* Department of Medicine and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, Australia; and
{dagger} Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia

1. Correspondence: Department of Medicine and CRC for Chronic Inflammatory Diseases, University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail: afl{at}unimelb.edu.au

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-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.