PMID- 30683864
OWN - NLM
STAT- MEDLINE
DCOM- 20200406
LR  - 20211204
IS  - 2041-4889 (Electronic)
VI  - 10
IP  - 2
DP  - 2019 Jan 25
TI  - Heme detoxification by heme oxygenase-1 reinstates proliferative and immune 
      balances upon genotoxic tissue injury.
PG  - 72
LID - 10.1038/s41419-019-1342-6 [doi]
LID - 72
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), H2AXgamma, 
      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.
FAU - Hedblom, Andreas
AU  - Hedblom A
AD  - Department of Surgery, Cancer Research Institute and Transplant Institute, Beth 
      Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
AD  - Department of Translational Medicine, Lund University, Lund, Sweden.
AD  - Department of Molecular Biology, Umea University, Umea, Sweden.
FAU - Hejazi, Seyed M
AU  - Hejazi SM
AD  - Department of Surgery, Cancer Research Institute and Transplant Institute, Beth 
      Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
FAU - Canesin, Giacomo
AU  - Canesin G
AD  - Department of Surgery, Cancer Research Institute and Transplant Institute, Beth 
      Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
FAU - Choudhury, Reeham
AU  - Choudhury R
AD  - Department of Surgery, Cancer Research Institute and Transplant Institute, Beth 
      Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
FAU - Hanafy, Khalid A
AU  - Hanafy KA
AD  - Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA, USA.
FAU - Csizmadia, Eva
AU  - Csizmadia E
AD  - Department of Surgery, Cancer Research Institute and Transplant Institute, Beth 
      Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
FAU - Persson, Jenny L
AU  - Persson JL
AD  - Department of Translational Medicine, Lund University, Lund, Sweden.
AD  - Department of Molecular Biology, Umea University, Umea, Sweden.
FAU - Wegiel, Barbara
AU  - Wegiel B
AD  - Department of Surgery, Cancer Research Institute and Transplant Institute, Beth 
      Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 
      bwegiel@bidmc.harvard.edu.
LA  - eng
GR  - R01 DK104714/DK/NIDDK NIH HHS/United States
GR  - R21 CA169904/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190125
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Cdkn2a protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Membrane Proteins)
RN  - 42VZT0U6YR (Heme)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (Hmox1 protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/*genetics
MH  - Cellular Senescence/genetics
MH  - Cyclin-Dependent Kinase Inhibitor p16/metabolism
MH  - DNA Damage/genetics
MH  - Gene Knockdown Techniques
MH  - Heme/*metabolism
MH  - Heme Oxygenase-1/genetics/*metabolism
MH  - Macrophages/*metabolism
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Phenotype
MH  - RAW 264.7 Cells
MH  - Radiation Injuries, Experimental/*immunology/*metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Transfection
PMC - PMC6347604
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/01/27 06:00
MHDA- 2020/04/09 06:00
PMCR- 2019/01/25
CRDT- 2019/01/27 06:00
PHST- 2018/12/28 00:00 [received]
PHST- 2019/01/02 00:00 [accepted]
PHST- 2019/01/27 06:00 [entrez]
PHST- 2019/01/27 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/01/25 00:00 [pmc-release]
AID - 10.1038/s41419-019-1342-6 [pii]
AID - 1342 [pii]
AID - 10.1038/s41419-019-1342-6 [doi]
PST - epublish
SO  - Cell Death Dis. 2019 Jan 25;10(2):72. doi: 10.1038/s41419-019-1342-6.