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

Hedblom, Andreas LU ; Hejazi, Seyed M.; Canesin, Giacomo LU ; Choudhury, Reeham; Hanafy, Khalid A.; Csizmadia, Eva; Persson, Jenny L. LU and Wegiel, Barbara LU (2019) In Cell Death and Disease 10(2).
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Death and Disease
volume
10
issue
2
publisher
Nature Publishing Group
external identifiers
  • scopus:85060524022
ISSN
2041-4889
DOI
10.1038/s41419-019-1342-6
language
English
LU publication?
yes
id
21cec4c7-f365-4730-a82e-7ac54206b436
date added to LUP
2019-02-05 11:54:14
date last changed
2019-02-27 05:12:19
@article{21cec4c7-f365-4730-a82e-7ac54206b436,
  abstract     = {<p>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<sup>INK4a</sup>, 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<sup>INK4a</sup> expression in macrophages, preventing DNA damage and cellular senescence.</p>},
  articleno    = {72},
  author       = {Hedblom, Andreas and Hejazi, Seyed M. and Canesin, Giacomo and Choudhury, Reeham and Hanafy, Khalid A. and Csizmadia, Eva and Persson, Jenny L. and Wegiel, Barbara},
  issn         = {2041-4889},
  language     = {eng},
  month        = {02},
  number       = {2},
  publisher    = {Nature Publishing Group},
  series       = {Cell Death and Disease},
  title        = {Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury},
  url          = {http://dx.doi.org/10.1038/s41419-019-1342-6},
  volume       = {10},
  year         = {2019},
}