Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence.
The proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) inhibits hematopoietic stem cell (HSC) expansion, interferes with HSC self-renewal and compromises the ability of HSC to reconstitute hematopoiesis. We have investigated mechanisms by which TNFalpha suppresses hematopoiesis using the genomic instability syndrome Fanconi anemia mouse model deficient for the complementation-group-C gene (Fancc). Examination of senescence makers, such as senescence-associated beta-galactosidase, HP1-gamma, p53 and p16(INK4A) shows that TNFalpha induces premature senescence in bone marrow HSCs and progenitor cells as well as other tissues of Fancc-/- mice. TNFalpha-induced senescence correlates with the accumulation of reactive oxygen species (ROS) and oxidative DNA damage. Neutralization of TNFalpha or deletion of the TNF receptor in Fancc-/- mice (Fancc-/-;Tnfr1-/-) prevents excessive ROS production and hematopoietic senescence. Pretreatment of TNFalpha-injected Fancc-/- mice with a ROS scavenger significantly reduces oxidative base damage, DNA strand breaks and senescence. Furthermore, HSCs and progenitor cells from TNFalpha-treated Fancc-/- mice show increased chromosomal aberrations and have an impaired oxidative DNA-damage repair. These results indicate an intimate link between inflammatory reactive oxygen species and DNA-damage-induced premature senescence in HSCs and progenitor cells, which may play an important role in aging and anemia.
Zhang
Xiaoling
X
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Sejas
Daniel P
DP
Qiu
Yuhui
Y
Williams
David A
DA
Pang
Qishen
Q
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D005199:Fanconi Anemia / Q000235:genetics / Q000473:pathology; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013154:Spleen / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D015238:Sulfotransferases / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000447:Aldehydes; C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C462359:tert-4-hydroxy-2-nonenal; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; D015238:Sulfotransferases; C028152:alcohol sulfotransferase; D003849:Deoxyguanosine; D000111:Acetylcysteine