Abstract
Reactive oxygen species (ROS) are formed by myeloid cells as a defense strategy against microorganisms. ROS however also trigger poly(ADP-ribose) polymerase 1- (PARP-1) dependent cell death (parthanatos) in adjacent lymphocytes, which has been forwarded as a mechanism of immune escape in several forms of cancer. The present study assessed the role of mitogen-activated protein kinases (MAPKs), in particular the extracellular signal-regulated kinase (ERK), in ROS-induced signal transduction leading to lymphocyte parthanatos. We report that inhibitors of ERK1/2 phosphorylation upheld natural killer (NK) cell-mediated cytotoxicity under conditions of oxidative stress and rescued NK cells and CD8+ T lymphocytes from cell death induced by ROS-producing monocytes. ERK1/2 phosphorylation inhibition also protected lymphocytes from cell death induced by exogenous hydrogen peroxide (H2O2) and from ROS generated by xanthine oxidase or glucose oxidase. Phosphorylation of ERK1/2 was observed in lymphocytes shortly after exposure to ROS. ROS-generating myeloid cells and exogenous H2O2 triggered PARP 1-dependent accumulation of poly ADP-ribose (PAR), which was prevented by ERK pathway inhibitors. ERK1/2 phosphorylation was induced by ROS independently of PARP-1. Our findings are suggestive of a role for ERK1/2 in ROS-induced lymphocyte parthanatos, and that the ERK axis may provide a therapeutic target for the protection of lymphocytes against oxidative stress.
Highlights
The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase transfers electrons from NADPH to molecular oxygen to produce superoxide anion, which is the substrate for a wide range of reactive oxygen species (ROS) including hydrogen peroxide (H2O2) [1]
We have previously reported that ROS-induced death of human natural killer (NK) cells and T cells is mediated by the poly(ADP-ribose) polymerase 1- (PARP-1)/apoptosis-inducing factor (AIF) axis [4], but details regarding signal transduction mechanisms upstream of DNA fragmentation and cell death have remained unknown
In accordance with the results obtained with lymphocytes exposed to H2O2, inhibition of the ERK1/2 pathway but not of JNK or p38 prevented cell death induced by ROS derived from xanthine oxidase or glucose oxidase (Figure S1G and 1H and data not shown)
Summary
The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase transfers electrons from NADPH to molecular oxygen to produce superoxide anion, which is the substrate for a wide range of reactive oxygen species (ROS) including hydrogen peroxide (H2O2) [1]. Superoxide anion and downstream ROS are produced in the phagosomes of several types of myeloid cells and contribute to the elimination of ingested microorganisms. The NADPH oxidase is present in the plasma membrane, leading to extracellular release of ROS that may damage neighboring cells. The ROS-induced inactivation of lymphocytes has been implicated in the development of autoimmunity and in cancerrelated immunosuppression. Myeloid cell-derived ROS have been ascribed a protective role in autoimmunity by eliminating autoreactive T cells, preventing arthritis [7,8]. Defining the intracellular signaling that transduces ROS-induced lymphocyte toxicity may have therapeutic implications
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