Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury
Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury
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DOI：
10.1038/s41419-019-1342-6
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发表时间：
2019-01-25
影响因子：
9
通讯作者：
Wegiel, Barbara
中科院分区：
文献类型：
--
作者：
Hedblom, Andreas;Hejazi, Seyed M.;Wegiel, Barbara
骨髓细胞的表型变化对于调节过早衰老、癌症的发展和对感染的反应至关重要。血红素代谢在骨髓细胞功能和活性的调节中具有重要作用。在这里，我们发现，血红素加氧酶-1 (HO-1)（一种去除血红素的酶）的缺失会导致 DNA 损伤反应 (DDR) 受损、细胞增殖减少和细胞衰老增加。我们检测到从 HO-1 缺陷小鼠分离的细胞和组织中 p16(INK4a)、H2AX gamma 和衰老相关 β-半乳糖苷酶 (SA-β-Gal) 水平升高。重要的是，嵌合小鼠巨噬细胞中 HO-1 的缺乏会导致 DNA 损伤增加，并在辐射诱导损伤时导致衰老。从机制上讲，我们发现哺乳动物雷帕霉素靶标 (mTOR)/S6 蛋白信号传导对于巨噬细胞的血红素和 HO-1 调节表型至关重要。总的来说，我们的数据表明 HO-1 通过解血红素，阻断巨噬细胞中 p16(INK4a) 的表达，防止 DNA 损伤和细胞衰老。
Phenotypic changes of myeloid cells are critical to the regulation of premature aging, development of cancer, and responses to infection. Heme metabolism has a fundamental role in the regulation of myeloid cell function and activity. Here, we show that deletion of heme oxygenase-1 (HO-1), an enzyme that removes heme, results in an impaired DNA damage response (DDR), reduced cell proliferation, and increased cellular senescence. We detected increased levels of p16(INK4a), H2AX gamma, and senescence-associated-beta-galactosidase (SA-beta-Gal) in cells and tissues isolated from HO-1-deficient mice. Importantly, deficiency of HO-1 in residential macrophages in chimeric mice results in elevated DNA damage and senescence upon radiation-induced injury. Mechanistically, we found that mammalian target of rapamycin (mTOR)/S6 protein signaling is critical for heme and HO-1-regulated phenotype of macrophages. Collectively, our data indicate that HO-1, by detoxifying heme, blocks p16(INK4a) expression in macrophages, preventing DNA damage and cellular senescence.