Abstract
Microglia as the primary immune cells of brain act protective effects against injuries and infections in the central nervous system. Inflammation via excessive Ca2+ influx and oxygen radical species (ROS) generation is a known factor in many neurodegenerative disorders. Importantly, the Ca2+ permeable TRPM2 channel is activated by oxidative stress. Thus, TRPM2 could provide the excessive Ca2+ influx in the microglia. Although TRPM2 expression level is high in inflammatory cells, the interplay between mouse microglia and TRPM2 channel during inflammation is not fully identified. Thus, it is important to understand the mechanisms and factors involved in order to enhance neuronal regeneration and repair. The data presented here indicate that TRPM2 channels were activated in microglia cells by interferon-gamma (IFNγ). The IFNγ treatment further increased apoptosis (early and late) and cytokine productions (TNF-α, IL-1β, and IL-6) which were due to increased lipid peroxidation and ROS generations as well as increased activations of caspase −3 (Casp-3) and − 9 (Casp-9). However, selenium treatment diminished activations of TRPM2, cytokine, Casp-3, and Casp-9, and levels of lipid peroxidation and mitochondrial ROS production in the microglia that were treated with IFNγ. Moreover, addition of either PARP1 inhibitors (PJ34 or DPQ) or TRPM2 blockers (2-APB or ACA) potentiated the modulator effects of selenium. These results clearly suggest that IFNγ leads to TRPM2 activation in microglia cells; whereas, selenium prevents IFNγ-mediated TRPM2 activation and cytokine generation. Together the interplay between IFNγ released from microglia cells is importance in brain inflammation and may affect oxidative cytotoxicity in the microglia.
Summary of pathways involved in IFNγ-induced TRPM2 activation and microglia death through excessive reactive oxygen species (ROS): Modulator role of selenium (Se). The IFNγ causes the microglia activation. Nudix box domain of TRPM2 is sensitive to ROS. The ROS induces DNA damage and ADPR-ribose (ADPR) production in the nucleus via PARP1 enzyme activation. ADPR and ROS-induced TRPM2 activation stimulates excessive Ca2+ influx. ROS are produced in the mitochondria through the increase of free cytosolic Ca2+ (via TRPM2 activation) by the IFNγ treatment, although they are diminished by the TRPM2 channel blocker (ACA and 2-APB) and PARP1 inhibitor treatments. The main mechanism in the cell death and inflammatory effects of IFNγ is mediated by stimulation of ROS-mediated caspase (caspase −3 and − 9) activations and cytokine production (TNF-α, IL-1β, and IL-6) via TRPM2 activation, respectively. The apoptotic, inflammatory, and oxidant actions of IFNγ are modulated through TRPM2 inhibition by the Se treatment
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The study was supported by BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture and Industry Ltd., Goller Bolgesi Teknokenti, Isparta, Turkey (Project No: 2018–30). There is no financial disclosure of the current study.
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MN and YA formulated the present hypothesis and MN were responsible for writing the report. KY was responsible for isolating the microglia and analyzing the cytokine and patch-clamp. MN was responsible for the laser confocal microscope analyses. YA was also responsible from plate reader analyses. YA made critical revision for the manuscript.
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Akyuva, Y., Nazıroğlu, M. & Yıldızhan, K. Selenium prevents interferon-gamma induced activation of TRPM2 channel and inhibits inflammation, mitochondrial oxidative stress, and apoptosis in microglia. Metab Brain Dis 36, 285–298 (2021). https://doi.org/10.1007/s11011-020-00624-0
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DOI: https://doi.org/10.1007/s11011-020-00624-0