Abstract
The transition from paraquat (PQ) to diquat (DQ), both organic dication herbicides, in China has led to significant increases in the number of acute DQ poisoning cases. Case studies have shown that acute DQ poisoning resulted in injury to the central nervous system (CNS), but the mechanism underlying the injury remains to be explored. The present study aimed to investigate how DQ influenced purinergic signaling between astrocytes and microglia and whether extracellular ATP (eATP) was involved in promoting neuroinflammation induced by acute DQ toxicity through the activation of the P2X4/NLRP3 signaling pathway. We constructed a rat model of acute DQ toxicity to observe the pathological changes in hippocampal tissues after DQ exposure and measure the expression levels of IL-1β and TNF-α in the hippocampal tissue. We also established an in vitro co-culture model of C6 astrocytes and BV-2 microglia using transwell chambers, measured the amount of eATP secreted into C6 astrocytes after DQ treatment, and assessed the inflammatory response and changes in the P2X4/NLRP3 signaling pathway in BV-2 microglia. The results showed that the neurons in the hippocampal tissue of rats exhibited loose arrangement, nuclear consolidation, and necrosis after DQ exposure, and IL-1β and TNF-α levels were signification higher in the hippocampal tissue after DQ exposure. DQ exposure to the co-cultured cells induced an increase in ATP secretion from C6 astrocytes as well as a significant increase of P2X4, NLRP3, IL-1β, and IL-18 expression in BV-2 microglia. In contrast, pretreatment of C6 astrocytes with apyrase (an ATP hydrolase) resulted in a significant decrease of P2X4, NLRP3, IL-1β, and IL-18 expression in BV-2 microglia. Furthermore, inhibition of P2X4 expression in BV-2 microglia by transfection with si-P2X4 effectively reversed the increase of NLRP3, IL-1β, and IL-18 in BV-2 microglia induced by DQ when co-cultured with C6 astrocytes. These results indicate that astrocytes can activate the P2X4/NLRP3 signaling pathway in microglia through the DQ-induced extracellular release of ATP to promote neuroinflammation in rat hippocampal tissue.
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Acknowledgements
This work was supported by the Hebei Science and Technology Bureau Project (project numbers 202230714010550). We thank Yuxia Ma of the Public Health College of Hebei Medical University for their support and guidance.
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All sources of funding for the research were declared. Hebei Science and Technology Bureau Project (project numbers 202230714010550).
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CQ: guarantor of integrity of the entire study, study concepts, study design, definition of intellectual content, literature research, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, manuscript review.
YY: literature research, data acquisition, data analysis, statistical analysis, manuscript editing.
QC: guarantor of integrity of the entire study, study concepts, study design, manuscript review.
LZ: study concepts, study design, manuscript review.
SL: study concepts, data analysis.
QY and QD: data analysis.
BS: guarantor of integrity of the entire study, study concepts, study design, definition of intellectual content, literature research, manuscript review.
BW: guarantor of integrity of the entire study, study concepts, study design, definition of intellectual content, manuscript review.
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Qi, C., Yan, Y., Cao, Q. et al. Elucidating the mechanisms underlying astrocyte-microglia crosstalk in hippocampal neuroinflammation induced by acute diquat exposure. Environ Sci Pollut Res 31, 15746–15758 (2024). https://doi.org/10.1007/s11356-024-31905-1
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DOI: https://doi.org/10.1007/s11356-024-31905-1