DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas
DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas
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DOI：
10.1016/j.cell.2016.09.054
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发表时间：
2016-11-17
期刊：
影响因子：
64.5
通讯作者：
Triantafyllopoulou, Antigoni
中科院分区：
文献类型：
--
作者：
Herrtwich, Laura;Nanda, Indrajit;Triantafyllopoulou, Antigoni
肉芽肿是响应于持续的炎症刺激而形成的免疫细胞聚集体。肉芽肿巨噬细胞亚群是多样的，并携带不同拷贝数的基因组信息。控制这种巨噬细胞群体响应于慢性刺激而分化的分子程序虽然对疾病结果至关重要，但尚未被定义。在这里，我们描绘了一个巨噬细胞分化途径，通过该途径，一个持久的Toll样受体（TLR）2信号通过诱导复制应激和激活DNA损伤反应来指导多倍体巨噬细胞的命运。多倍体肉芽肿驻留巨噬细胞通过修饰的细胞分裂和有丝分裂缺陷形成，而不是像以前认为的那样，通过细胞与细胞融合形成。TLR2信号通过调节Myc和ATR促进巨噬细胞多倍化并抑制基因组不稳定性。我们认为，在持续性炎症刺激的存在下，以前与癌基因启动的致癌作用相关的途径指导了一个长期存在的肉芽肿驻留巨噬细胞分化程序，该程序调节肉芽肿组织重塑。
Granulomas are immune cell aggregates formed in response to persistent inflammatory stimuli. Granuloma macrophage subsets are diverse and carry varying copy numbers of their genomic information. The molecular programs that control the differentiation of such macrophage populations in response to a chronic stimulus, though critical for disease outcome, have not been defined. Here, we delineate a macrophage differentiation pathway by which a persistent Toll-like receptor (TLR)2 signal instructs polyploid macrophage fate by inducing replication stress and activating the DNA damage response. Polyploid granuloma-resident macrophages formed via modified cell divisions and mitotic defects and not, as previously thought, by cell-to-cell fusion. TLR2 signaling promoted macrophage polyploidy and suppressed genomic instability by regulating Myc and ATR. We propose that, in the presence of persistent inflammatory stimuli, pathways previously linked to oncogene-initiated carcinogenesis instruct a long-lived granuloma-resident macrophage differentiation program that regulates granulomatous tissue remodeling.