Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

Abstract

The proinflammatory cytokine tumor necrosis factor α (TNFα) 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 TNFα 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 β-galactosidase, HP1-γ, p53 and p16INK4A shows that TNFα induces premature senescence in bone marrow HSCs and progenitor cells as well as other tissues of Fancc–/– mice. TNFα-induced senescence correlates with the accumulation of reactive oxygen species (ROS) and oxidative DNA damage. Neutralization of TNFα or deletion of the TNF receptor in Fancc–/– mice (Fancc–/–;Tnfr1–/–) prevents excessive ROS production and hematopoietic senescence. Pretreatment of TNFα-injected Fancc–/– mice with a ROS scavenger significantly reduces oxidative base damage, DNA strand breaks and senescence. Furthermore, HSCs and progenitor cells from TNFα-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.

Enrichment of hematopoietic stem cells with SLAM and LSK markers for the detection of hematopoietic stem cell function in normal and Trp53 null mice

“…Our results are in agreement with a recent report by Jang et al, in which primitive HSCs had lower levels of ROS whereas ROS hi cells display signs of HSC exhaustion through serial transplantation [21]. In a mouse model of Fanconi anemia, administration of the proinflammatory cytokine tumor necrosis factor alpha induced premature senescence in BM HSCs, progenitor cells with higher Trp53, higher level of ROS, and more oxidative DNA damage [22]. The fact that SLAM cells are highly enriched for HSCs by CR and serial transplantation assessments provided definitive evidence showing that CD150-based SLAM markers are a useful set of markers effective for the enrichment of long-term functional HSCs, consistent with the original report showing much higher HSC activity in CD150 + BM cells [4].…”

Prevention of Bone Marrow Cell Apoptosis and Regulation of Hematopoiesis by Type I IFNs during Systemic Responses to Pneumocystis Lung Infection

“…Baseline ROS production indeed increased in BM cells from IFrag 2/2 but not loss and dysfunction resulted in lack of band neutrophil replenishment. Models for inherited BM-failure diseases, such as Fanconi anemia, have demonstrated an increased sensitivity to inflammation-induced (TNF-a mediated) ROS production in hematopoietic precursor cells (34,49) and protection from BM failure via antioxidant treatment. Antioxidant treatment of IFrag 2/2 mice during Pneumocystis lung infection also significantly suppressed ROS production in BM cells.…”

Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

“…This seems to be mediated through TNF-α-induced senescence that correlates with the accumulation of ROS and oxidative DNA damage (44). Interestingly, FANCC seems to be involved both in the protection of cells against oxidative damage and in the control of TNF-α activity (45).…”