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

Hedblom, AndreasUmeå University,Lund University,Lunds universitet,Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Translational Medicine, Lund University, Lund, Sweden,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups (author)

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.

Hejazi, Seyed M.Harvard University,Beth Israel Deaconess Medical Center (author)
Canesin, GiacomoBeth Israel Deaconess Medical Center,Harvard University(Swepub:lu)med-gcc (author)
Choudhury, ReehamHarvard University,Beth Israel Deaconess Medical Center (author)
Hanafy, Khalid A.Harvard University (author)
Csizmadia, EvaHarvard University,Beth Israel Deaconess Medical Center (author)
Persson, Jenny L.Umeå University,Lund University,Lunds universitet,Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Department of Translational Medicine, Lund University, Lund, Sweden,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups(Swepub:lu)medk-jpe (author)
Wegiel, BarbaraBeth Israel Deaconess Medical Center,Harvard University(Swepub:lu)med-bwe (author)
Umeå universitetInstitutionen för molekylärbiologi (Medicinska fakulteten) (creator_code:org_t)

By the author/editor: Hedblom, Andreas; Hejazi, Seyed M.; Canesin, Giacomo; Choudhury, Reeha ...; Hanafy, Khalid A ...; Csizmadia, Eva; show more...; Persson, Jenny L ...; Wegiel, Barbara; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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