GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on Type I interferon signaling
GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on Type I interferon signaling
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DOI：
10.1189/jlb.1108702
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发表时间：
2009-08-01
影响因子：
5.5
通讯作者：
Hamilton, John A.
中科院分区：
文献类型：
--
作者：
Fleetwood, Andrew J.;Dinh, Hang;Hamilton, John A.
M-CSF和GM-CSF是参与调节巨噬细胞谱系群体的数量和功能的介质，并且已显示有助于巨噬细胞异质性。I型IFN是由巨噬细胞产生的重要介质，并且可以对其性质具有深刻的调节作用。在这项研究中，我们比较了骨髓源性巨噬细胞（BMM）和GM-CSF诱导的BMM（GM-BMM）从野生型和IFNAR 1（-/-）小鼠，以评估内源性I型IFN的BMM和GM-BMM之间的表型差异的贡献。BMM能够产生更高的组成型IFN-β，这对它们的基础转录组有显著贡献。微阵列分析发现，在BMM或GM-BMM特异性的内源性I型IFN调节基因中，488个基因改变是BMM独有的，而只有50个是GM-BMM独有的。此外，相对于GM-BMM，BMM显示出许多被鉴定为依赖于I型IFN信号传导的基因（包括Stat 1、Stat 2、Irf 7、Ccl 5、Ccl 12和Cxcl 10）的基础mRNA水平增强。作为先前I型IFN“引发”的结果，在LPS刺激后，与GM-BMM相比，BMM显示MyD 88非依赖性IRF-3/STAT 1途径的活化增加，这与两个巨噬细胞亚群的不同细胞因子/趋化因子谱相关。此外，自分泌I型IFN信号环调节M1和M2特征细胞因子IL-12 p70和IL-10的产生。总的来说，这些研究结果表明，组成型和LPS诱导的I型IFN在调节BMM和GM-BMM之间的表型和功能的差异中发挥重要作用。J. Leukoc. 86：411-421; 2009.
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. J. Leukoc. Biol. 86: 411-421; 2009.