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Reactive oxygen species play a role in P2X7 receptor-mediated IL-6 production in spinal astrocytes

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Abstract

Astrocytes mediate a remarkable variety of cellular functions, including gliotransmitter release. Under pathological conditions, high concentrations of the purinergic receptor agonist adenosine triphosphate (ATP) are released into the extracellular space leading to the activation of the purinergic P2X7 receptor, which in turn can initiate signaling cascades. It is well-established that reactive oxygen species (ROS) increase in macrophages and microglia following P2X7 receptor activation. However, direct evidence that activation of P2X7 receptor leads to ROS production in astrocytes is lacking to date. While it is known that P2X7R activation induces cytokine production, the mechanism involved in this process is unclear. In the present study, we demonstrated that P2X7 receptor activation induced ROS production in spinal astrocytes in a concentration-dependent manner. We also found that P2X7R-mediated ROS production is at least partially through NADPH oxidase. In addition, our ELISA data show that P2X7R-induced IL-6 release was dependent on NADPH oxidase-mediated production of ROS. Collectively, these results reveal that activation of the P2X7 receptor on spinal astrocytes increases ROS production through NADPH oxidase, subsequently leading to IL-6 release. Our results reveal a role of ROS in the P2X7 signaling pathway in mouse spinal cord astrocytes and may indicate a potential mechanism for the astrocytic P2X7 receptor in chronic pain.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA

    Frances M. Munoz, Priya A. Patel, Jingsheng Xia & Huijuan Hu

  2. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China

    Xinghua Gao

  3. Department of Anesthesiology, Rutgers New Jersey Medical School, 185 S. Orange Ave., Newark, NJ, 07103, USA

    Yixiao Mei, Sofia Gilels & Huijuan Hu

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  1. Frances M. Munoz
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This work was supported by NIH Grants R21NS077330 and R01NS087033 to H.H.

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All experiments were performed in accordance with the guidelines of the National Institutes of Health (NIH) and with the guidelines of the Committee for Research and Ethical Issues of IASP and were approved by the Animal Care and Use Committee of Rutgers New Jersey Medical School.

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Munoz, F.M., Patel, P.A., Gao, X. et al. Reactive oxygen species play a role in P2X7 receptor-mediated IL-6 production in spinal astrocytes. Purinergic Signalling 16, 97–107 (2020). https://doi.org/10.1007/s11302-020-09691-5

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