Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury

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Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury. / Hedblom, Andreas; Hejazi, Seyed M.; Canesin, Giacomo; Choudhury, Reeham; Hanafy, Khalid A.; Csizmadia, Eva; Persson, Jenny L.; Wegiel, Barbara.

I: Cell Death and Disease, Vol. 10, Nr. 2, 72, 01.02.2019.

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Hedblom, Andreas ; Hejazi, Seyed M. ; Canesin, Giacomo ; Choudhury, Reeham ; Hanafy, Khalid A. ; Csizmadia, Eva ; Persson, Jenny L. ; Wegiel, Barbara. / Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury. I: Cell Death and Disease. 2019 ; Vol. 10, Nr. 2.

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TY - JOUR

T1 - Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury

AU - Hedblom, Andreas

AU - Hejazi, Seyed M.

AU - Canesin, Giacomo

AU - Choudhury, Reeham

AU - Hanafy, Khalid A.

AU - Csizmadia, Eva

AU - Persson, Jenny L.

AU - Wegiel, Barbara

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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 p16INK4a, H2AXγ, and senescence-associated-β-galactosidase (SA-β-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 p16INK4a expression in macrophages, preventing DNA damage and cellular senescence.

AB - 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 p16INK4a, H2AXγ, and senescence-associated-β-galactosidase (SA-β-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 p16INK4a expression in macrophages, preventing DNA damage and cellular senescence.

U2 - 10.1038/s41419-019-1342-6

DO - 10.1038/s41419-019-1342-6

M3 - Article

VL - 10

JO - Cell Death & Disease

T2 - Cell Death & Disease

JF - Cell Death & Disease

SN - 2041-4889

IS - 2

M1 - 72

ER -