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

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

N1 - Publisher Copyright: © 2019, The Author(s).

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 p16 INK4a , 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 p16 INK4a 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 p16 INK4a , 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 p16 INK4a expression in macrophages, preventing DNA damage and cellular senescence.

UR - https://www.scopus.com/pages/publications/85060524022

UR - https://www.scopus.com/pages/publications/85060524022#tab=citedBy

U2 - 10.1038/s41419-019-1342-6

DO - 10.1038/s41419-019-1342-6

M3 - Article

C2 - 30683864

SN - 2041-4889

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 2

M1 - 72

ER -