Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity
Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity
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DOI：
10.1016/j.immuni.2019.09.002
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发表时间：
2019-10-15
期刊：
影响因子：
32.4
通讯作者：
Glass, Christopher K.
中科院分区：
文献类型：
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作者：
Sakai, Mashito;Troutman, Ty D.;Glass, Christopher K.
组织环境在建立和维持常驻巨噬细胞的独特表型中起着重要作用，但其潜在的分子机制仍知之甚少。在这里，我们的特点是转录组和表观遗传学的变化，在急性枯否细胞耗竭后，作为一种手段，推断信号通路和转录因子，促进枯否细胞分化的重新填充肝巨噬细胞。我们获得的证据表明，Notch配体DLL 4和转化生长因子-b（TGF-β）家族的窦状内皮细胞和内源性LXR配体产生的配体的组合相互作用所需的诱导和维持枯否细胞的身份。DLL 4对Notch转录效应子RBPJ的调节激活了平衡的增强子，以快速诱导LXR α和其他库普弗细胞谱系决定因子。这些因子反过来重新编程重新填充的肝脏巨噬细胞增强子景观，以收敛于原始的常驻枯否细胞。总的来说，这些发现为理解巨噬细胞祖细胞如何获得组织特异性表型提供了一个框架。
Tissue environment plays a powerful role in establishing and maintaining the distinct phenotypes of resident macrophages, but the underlying molecular mechanisms remain poorly understood. Here, we characterized transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. We obtained evidence that combinatorial interactions of the Notch ligand DLL4 and transforming growth factor-b (TGF-beta) family ligands produced by sinusoidal endothelial cells and endogenous LXR ligands were required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of the Notch transcriptional effector RBPJ activated poised enhancers to rapidly induce LXR alpha and other Kupffer cell lineage-determining factors. These factors in turn reprogrammed the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.