Coordinate effects of P2X7 and extracellular acidification in microglial cells
Ponarulselvam Sekar1, Duen-Yi Huang2, Shwu-Fen Chang1
1Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
Abstract:
Extracellular adenosine 5'-triphosphate (ATP) is a damage-associated molecular pattern and contributes to inflammation associated diseases including cancer. Extracellular acidosis is a novel danger signal in the inflammatory sites, where it can modulate inflammation, immunity and tumor growth. Extracellular acidification was shown to inhibit P2X7-mediated channel currents, while it remains unknown how acidification and P2X7 together affect cellular responses. Here, we treated BV-2 microglial cells with ATP in a short period (<15 min) or a sustained acidified condition. For short acidification we compared the actions of neutralized ATP and acidic ATP in a condition with pH buffering. For sustained acidification, we treated cells with neutralized ATP in acidic medium or acidic ATP in medium without pH buffering. In the short acidified condition, neutralized ATP induced higher responses than acidic ATP to increase intracellular calcium and reactive oxygen species, decrease intracellular potassium and induce cell death. In contrast, these cellular responses and mitochondrial fission caused by neutralized ATP were enhanced by pH 6.0 and pH 4.5 media. P2X7 activation can also rapidly block mitochondrial ATP turnover and respiration capacity, both of which were mimicked by nigericin and enhanced by acidity. Taken together P2X7-mediated ionic fluxes and reactive oxygen species production are attenuated under short acidification, while sustained acidification itself can induce mitochondrial toxicity which deteriorates the mitochondrial function under P2X7 activation.
Insights
Extracellular acidosis impacts inflammation and cancer. Sustained acidity, not short-term, worsens P2X7 receptor-mediated cell damage and mitochondrial dysfunction, highlighting acidity
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Extracellular adenosine 5'-triphosphate (ATP) acts as a damage-associated molecular pattern, promoting inflammation and cancer.
- Extracellular acidosis is an emerging danger signal influencing inflammation, immunity, and tumor progression.
- The combined effects of acidosis and P2X7 receptor activation on cellular responses remain largely unexplored.
Purpose of the Study:
- To investigate how extracellular acidosis modulates cellular responses to adenosine 5'-triphosphate (ATP) via P2X7 receptor activation.
- To differentiate the impact of short-term versus sustained extracellular acidification on P2X7-mediated cellular events.
- To elucidate the role of acidosis in P2X7-induced mitochondrial dysfunction.
Main Methods:
- Treatment of BV-2 microglial cells with ATP under varying pH conditions (short-term and sustained acidification).
- Assessment of intracellular calcium levels, reactive oxygen species production, intracellular potassium levels, and cell death.
- Evaluation of mitochondrial function, including ATP turnover and respiration capacity, and mitochondrial fission.
- Comparison of responses to neutralized and acidic ATP under buffered and unbuffered conditions.
Main Results:
- Under short-term acidification, neutralized ATP induced greater cellular responses than acidic ATP.
- Sustained acidification (pH 6.0 and 4.5) enhanced ATP-induced cellular responses and mitochondrial fission.
- P2X7 activation rapidly impaired mitochondrial ATP turnover and respiration, effects exacerbated by acidity.
- Short acidification attenuated P2X7-mediated ionic fluxes and reactive oxygen species production.
Conclusions:
- P2X7 receptor-mediated ionic fluxes and reactive oxygen species production are reduced under short-term acidification.
- Sustained extracellular acidosis induces mitochondrial toxicity, exacerbating P2X7 activation-induced mitochondrial dysfunction.
- Acidosis plays a complex role in P2X7 receptor signaling, with sustained acidity posing a greater threat to cellular and mitochondrial health in inflammatory contexts.
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