核受体PPARγ控制进行性巨噬细胞极化作为转录记忆的配体不敏感表观基因棘轮。**
巨噬细胞根据复杂的环境提示极化成不同的表型。我们发现核受体PPARγ在白介素(IL)-4反复刺激后,在巨噬细胞中产生了强大的表型变化。在这种情况下,PPARγ对巨噬细胞极化的功能与配体结合无关。对配体不敏感的PPARγ结合DNA,并募集了共激活因子P300和建筑蛋白RAD21。这建立了允许的染色质环境,通过促进转录调节因子STAT6和RNA聚合酶II的结合而赋予了转录记忆,从而在IL-4重新刺激时导致了增强子和mRNA的大量产生。配体不敏感的PPARγ结合控制巨噬细胞中细胞外基质重塑相关基因网络的表达。这些基因的表达在小鼠损伤模型的肌肉再生过程中增加,并且这种增加与在受影响的组织中检测到IL-4和PPARγ一致。因此,主要是对配体不敏感的PPARγ:RXR Cistrome调节进行性和/或增强性巨噬细胞极化。**
The Nuclear Receptor PPARγ Controls Progressive Macrophage Polarization as a Ligand-Insensitive Epigenomic Ratchet of Transcriptional Memory
Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPARγ drove robust phenotypic changes in macrophages upon repeated stimulation with interleukin (IL)-4. The functions of PPARγ on macrophage polarization in this setting were independent of ligand binding. Ligand-insensitive PPARγ bound DNA and recruited the coactivator P300 and the architectural protein RAD21. This established a permissive chromatin environment that conferred transcriptional memory by facilitating the binding of the transcriptional regulator STAT6 and RNA polymerase II, leading to robust production of enhancer and mRNAs upon IL-4 re-stimulation. Ligand-insensitive PPARγ binding controlled the expression of an extracellular matrix remodeling-related gene network in macrophages. Expression of these genes increased during muscle regeneration in a mouse model of injury, and this increase coincided with the detection of IL-4 and PPARγ in the affected tissue. Thus, a predominantly ligand-insensitive PPARγ:RXR cistrome regulates progressive and/or reinforcing macrophage polarization.
pmid: 30332629 Immunity 影响因子: 21.841 发表日期: 20181016 官网 免费下载 全文下载
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