Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner
Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner
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DOI：
10.15252/embj.201489293
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发表时间：
2014-12-17
期刊：
影响因子：
11.4
通讯作者：
Schwartz, Michal
中科院分区：
文献类型：
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作者：
Cohen, Merav;Matcovitch, Orit;Schwartz, Michal
组织微环境影响常驻和浸润性髓源性细胞的功能。在中枢神经系统（CNS）中，常驻小胶质细胞和新募集的浸润性单核细胞源性巨噬细胞（mo-M Phi）在病理条件下表现出不同的活动，但对调节这些差异的微环境源性分子机制知之甚少。在这里，我们证明了长期暴露于转化生长因子- β 1 （TGF β 1）会损害髓细胞获得解决抗炎表型的能力。通过全基因组表达分析和染色质免疫沉淀以及下一代测序，我们发现进行促抗炎（M1-to- M2）表型转换的能力是由转录因子干扰素调节因子7 （IRF7）控制的，该因子被TGFb1通路下调。rnai介导的Irf7的扰动抑制了m1到m2的转换，而IFN β 1 （Irf7通路激活剂）恢复了它。脊髓损伤后，体内诱导小胶质细胞中Irf7的表达可降低其促炎活性。这些结果强调了组织特异性环境因素在生理和病理条件下决定常驻髓源性细胞命运的关键作用。
Tissue microenvironment influences the function of resident and infiltrating myeloid-derived cells. In the central nervous system (CNS), resident microglia and freshly recruited infiltrating monocyte-derived macrophages (mo-M Phi) display distinct activities under pathological conditions, yet little is known about the microenvironment-derived molecular mechanism that regulates these differences. Here, we demonstrate that long exposure to transforming growth factor-beta 1 (TGF beta 1) impaired the ability of myeloid cells to acquire a resolving anti-inflammatory phenotype. Using genome-wide expression analysis and chromatin immunoprecipitation followed by next-generation sequencing, we show that the capacity to undergo pro-to anti-inflammatory (M1-to- M2) phenotype switch is controlled by the transcription factor interferon regulatory factor 7 (IRF7) that is down-regulated by the TGFb1 pathway. RNAi-mediated perturbation of Irf7 inhibited the M1-to-M2 switch, while IFN beta 1 (an IRF7 pathway activator) restored it. In vivo induction of Irf7 expression in microglia, following spinal cord injury, reduced their pro-inflammatory activity. These results highlight the key role of tissue-specific environmental factors in determining the fate of resident myeloid-derived cells under both physiological and pathological conditions.