NADPH oxidase 4 mediates ROS production in radiation-induced senescent cells and promotes migration of inflammatory cells

Abstract

Excessive DNA damage induced by ionising radiation (IR) to normal tissue cells is known to trigger cellular senescence, a process termed stress-induced premature senescence (SIPS). SIPS is often accompanied by the production of reactive oxygen species (ROS), and this is reported to be important for the initiation and maintenance of SIPS. However, the source of ROS during SIPS after IR and their significance in radiation-induced normal tissue damage remain elusive. In the present study, we tested the hypothesis that the NADPH oxidase (NOX) family of proteins mediates ROS production in SIPS-induced cells after IR and plays a role in SIPS-associated biological events. X-irradiation of primary mouse embryonic fibroblasts (MEFs) resulted in cellular senescence and the concomitant increase of intracellular ROS. Among all six murine NOX isoforms (NOX1-4 and DUOX1/2), only NOX4 was detectable under basal conditions and was upregulated following IR. In addition, radiation-induced ROS production was diminished by genetic or pharmacological inhibition of NOX4. Meanwhile, NOX4 deficiency did not affect the induction of cellular senescence after IR. Furthermore, the migration of human monocytic U937 cells to the culture medium collected from irradiated MEFs was significantly reduced by NOX4 inhibition, suggesting that NOX4 promotes the recruitment of inflammatory cells. Collectively, our findings imply that NOX4 mediates ROS production in radiation-induced senescent cells and contributes to normal tissue damage after IR via the recruitment of inflammatory cells and the exacerbation of tissue inflammation.

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“…ROS can be derived from different sources, including the mitochondria electron transport chain, xanthine oxidase, the cytochrome P450 system, uncoupled nitric oxide synthase, and myeloperoxidase. ROS also mainly comes from two main parts, mitochondrial and NADPH oxidase after radiation ( Bedard and Krause, 2007 ; Bhattacharyya et al., 2014 ; Cho et al., 2017 ; Pei et al., 2017 ; Kawamura et al., 2018 ; Sakai et al., 2018 ; Shimura et al., 2018 ; Mortezaee et al., 2019 ). To explore the origin of ROS induced by 1α,25(OH) 2 D 3 , both NADPH oxidase inhibitors, DPI and Apocynin, and the mitochondrial membrane potential were used to determine the source of ROS ( Bedard and Krause, 2007 ).…”

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“…For example, upregulation of Nox4 by ionizing radiation induces SIPS in MEFs. Nox4-derived ROS production was associated with increased migration of monocytes, supporting a role of ROS in the recruitment of inflammatory cells into irradiated tissues [ 106 ]. In endothelial cells, upregulation of Nox4 during aging causes endothelial dysfunction mediated by endoplasmic reticulum (ER) stress, leading to eNOS uncoupling [ 107 ].…”

A Comprehensive Analysis of Near‐Contact Photobiomodulation Therapy in the Host–Bacteria Interaction Model Using 3D‐Printed Modular LED Platform

“…Therefore, it seems that the major inhibition pathway of anti‐inflammation by R or NIR irradiation is through Nox4‐MyD88‐NF‐κB in this model (see Figure S4, Supporting Information). It has been reported that ionizing radiation or blue light (405 nm) irradiation exhibited enhancement of Nox4 expression level and ROS production, while those induced ROS productions could be diminished by inhibiting Nox4 expression level genetically or pharmacologically 51,52. Our data showed that the production of ROS can be regulated by R or NIR irradiation without using any drugs, indicating a potent of PBM therapy as a Nox4 regulator.…”