title: Death of Monocytes through Oxidative Burst of Macrophages and Neutrophils: Killing in Trans.
abstract: Monocytes and their descendants, macrophages, play a key role in the defence against pathogens. They also contribute to the pathogenesis of inflammatory diseases. Therefore, a mechanism maintaining a balance in the monocyte/macrophage population must be postulated. Our previous studies have shown that monocytes are impaired in DNA repair, rendering them vulnerable to genotoxic stress while monocyte-derived macrophages are DNA repair competent and genotoxic stress-resistant. Based on these findings, we hypothesized that monocytes can be selectively killed by reactive oxygen species (ROS) produced by activated macrophages. We also wished to know whether monocytes and macrophages are protected against their own ROS produced following activation. To this end, we studied the effect of the ROS burst on DNA integrity, cell death and differentiation potential of monocytes. We show that monocytes, but not macrophages, stimulated for ROS production by phorbol-12-myristate-13-acetate (PMA) undergo apoptosis, despite similar levels of initial DNA damage. Following co-cultivation with ROS producing macrophages, monocytes displayed oxidative DNA damage, accumulating DNA single-strand breaks and a high incidence of apoptosis, reducing their ability to give rise to new macrophages. Killing of monocytes by activated macrophages, termed killing in trans, was abolished by ROS scavenging and was also observed in monocytes co-cultivated with ROS producing activated granulocytes. The data revealed that monocytes, which are impaired in the repair of oxidised DNA lesions, are vulnerable to their own ROS and ROS produced by macrophages and granulocytes and support the hypothesis that this is a mechanism regulating the amount of monocytes and macrophages in a ROS-enriched inflammatory environment.
authors.affiliation: Department of Toxicology, University Medical Center, Mainz, Germany.
authors.forename: Viviane
authors.initials: V
authors.lastname: Ponath
authors.affiliation: Department of Toxicology, University Medical Center, Mainz, Germany.
authors.forename: Bernd
authors.identifier: http://orcid.org/0000-0002-8217-0809
authors.initials: B
authors.lastname: Kaina
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D010703:Phorbol Esters; D017382:Reactive Oxygen Species; D000076105:X-ray Repair Cross Complementing Protein 1; C119222:phorbol-12-myristate; D011064:Poly Adenosine Diphosphate Ribose; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1