Human monocytes are severely impaired in base and DNA double-strand break repair that renders them vulnerable to oxidative stress

Abstract

Monocytes are key players in the immune system. Crossing the blood barrier, they infiltrate tissues and differentiate into (i) macrophages that fight off pathogens and (ii) dendritic cells (DCs) that activate the immune response. A hallmark of monocyte/macrophage activation is the generation of reactive oxygen species (ROS) as a defense against invading microorganisms. How monocytes, macrophages, and DCs in particular respond to ROS is largely unknown. Here we studied the sensitivity of primary human monocytes isolated from peripheral blood and compared them with macrophages and DCs derived from them by cytokine maturation following DNA damage induced by ROS. We show that monocytes are hypersensitive to ROS, undergoing excessive apoptosis. These cells exhibited a high yield of ROS-induced DNA single-and double-strand breaks and activation of the ATR-Chk1-ATM-Chk2-p53 pathway that led to Fas and caspase-8, -3, and -7 activation, whereas macrophages and DCs derived from them were protected. Monocytes are also hypersensitive to ionizing radiation and oxidized low-density lipoprotein. The remarkable sensitivity of monocytes to oxidative stress is caused by a lack of expression of the DNA repair proteins XRCC1, ligase IIIα, poly (ADP-ribose) polymerase-1, and catalytic subunit of DNA-dependent protein kinase (DNA-PK cs ), causing a severe DNA repair defect that impacts base excision repair and double-strand break repair by nonhomologous end-joining. During maturation of monocytes into macrophages and DCs triggered by the cytokines GM-CSF and IL-4, these proteins become up-regulated, making macrophages and DCs repair-competent and ROS-resistant. We propose that impaired DNA repair in monocytes plays a role in the regulation of the monocyte/macrophage/DC system following ROS exposure.DNA damage response | monocytes | macrophages | dendritic cells

NBS1 is required for macrophage homeostasis and functional activity in mice

“…Monocytes are more prone to DNA damage than dendritic cells and macrophages, exhibiting increased apoptosis upon ROS exposure resulting from impaired DSB repair. 46 Because Nbs1 ΔB/ΔB mice have defective DSB responses, it is possible that over time, DNA damage is accumulated in monocytes and macrophages.…”

Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes

“…These cells originate from the bone marrow and are then released into the bloodstream following maturation, while in tissues, they differentiate into macrophages and myeloid dendritic cells (DCs) (6). Monocytes are important in antigen presentation, release of immune-regulatory cytokines, T-cell stimulation and differentiation, thus orchestrating the immune system in response to ̔attacking signals̛ (7). Toll-like receptors (TLRs) are crucial in initiating an immune response in monocytes.…”

Polymorphisms in DNA Repair Gene XRCC1 (Arg194Trp) and (Arg399Gln) and their Role in the susceptibility of Bacterial Meningitis

“…After the differentiation in macrophages and dendritic cells, the repair proteins levels are restored. The authors proposed that the deficiency in repair of monocytes may be important to the regulation of inflammatory response, since the selective killing of monocytes during oxidative stress induced by macrophage may act as a negative regulatory feedback, reducing the macrophage differentiation and avoiding the excess of oxidative stress during inflammation [38]. In this scenario, it could be important to investigate the effect of the XRCC1 Gln variant in monocytes/ macrophage differentiation process.…”