Abstract:
Low-oxygen conditions (hypoxia) have been associated primarily with cell-cycle arrest in dividing cells. Macrophages are typically quiescent in G0 but can proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in macrophages. Cell cycle progression is largely limited to G0-G1/S phase transition with little progression to G2/M. This cell cycle transitioning is triggered by an HIF2α-directed transcriptional program. The response is accompanied by increased expression of cell-cycle-associated proteins, including CDK1, which is known to phosphorylate SAMHD1 at T592 and thereby regulate antiviral activity. Prolyl hydroxylase (PHD) inhibitors are able to recapitulate HIF2α-dependent cell cycle entry in macrophages. Finally, tumor-associated macrophages (TAMs) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at the single-cell level. These findings have implications for inflammation and tumor progression/metastasis where low-oxygen environments are common.
摘要:
低氧条件(缺氧)主要与分裂细胞中的细胞周期停滞有关。巨噬细胞在G0中通常是静止的,但可以响应于组织信号而增殖。在这里,我们显示缺氧(1%氧分压)导致巨噬细胞可逆进入细胞周期。细胞周期进程在很大程度上限于G0-G1/S相变,几乎没有进展到G2/M。这种细胞周期转变由HIF2α指导的转录程序触发。这种反应伴随着细胞周期相关蛋白的表达增加,包括CDK1,已知CDK1在T592磷酸化SAMHD1,从而调节抗病毒活性。丙基羟化酶(PHD)抑制剂能够概括巨噬细胞中HIF2α依赖性细胞周期的进入。最后,肺癌中的肿瘤相关巨噬细胞(TAM)表现出转录组特征,代表在单细胞水平对低氧和细胞周期进程的反应.这些发现对低氧环境常见的炎症和肿瘤进展/转移有影响。