ATP/P2X4 Regulates Inflammation and Oxidative Stress in Endometriosis Through NLRP3 Inflammasome-Dependent Mechanisms

Tingting Wu, Wu T, Guo Y, Yan Guo
American journal of reproductive immunology (New York, N.Y. : 1989) · 2025 · vol. 94(2) , pp. e70132 · doi:10.1111/aji.70132 · PMID:40815040 · W4413139624
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This study found that ATP/P2X4 activation of the NLRP3 inflammasome increases inflammation and oxidative stress in endometriosis by upregulating IL-1β, TNF-α, IL-6, MDA, and ROS while decreasing SOD, GSH-Px, and CAT.

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This study investigated the role of ATP and P2X4 receptors in modulating inflammation and oxidative stress within endometriosis. Researchers analyzed ectopic and normal endometrial tissues and cells, finding that ATP and P2X4 were significantly upregulated in endometriotic samples. Inhibiting P2X4 with 5-BDBD or knocking it down reduced calcium levels, pro-inflammatory cytokines, and reactive oxygen species while enhancing antioxidant enzyme activity in ectopic endometrial stromal cells. The authors concluded that the ATP/P2X4 axis exacerbates these pathological features by activating the NLRP3 inflammasome, an effect that could be reversed by specific antagonists. This paper is centrally about endometriosis — specifically examining the molecular mechanisms driving inflammation and oxidative stress in ectopic endometrial tissue.

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Abstract

PURPOSE: Endometriosis (EMS) is a chronic inflammatory disorder with ectopic endometrial tissues arising in extrauterine areas. We investigated the mechanism of adenosine triphosphate (ATP)/P2X4 regulating inflammation and oxidative stress in EMS. METHODS: Normal endometrial tissues and ectopic endometrial tissues were collected, and determined for P2X4 expression by immunohistochemical staining. Normal (nESCs) and ectopic endometrial stromal cells (eESCs) were isolated and manipulated with Apyrase (a soluble ATP-diphosphohydrolase), 5-BDBD (a P2X4 receptor antagonist), or Nigericin (a NOD-like receptor 3 [NLRP3] inflammasome activator). The ATP concentration in endometrial tissues and cells were assessed through the ATP colorimetric/fluorescence assay, and cellular P2X4 expression was determined by RT-qPCR. Fluo 3-AM calcium ion fluorescence probe was utilized for detecting calcium ion concentration. Levels of inflammation-associated proteins (interleukin [IL]-1β, tumor necrosis factor-alpha [TNF-α], IL-6, IL-18), oxidative stress indicators (malondialdehyde [MDA], superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GSH-Px]), reactive oxygen species (ROS), and the NLRP3 inflammasome pathway-related proteins were determined by ELISA, DCFH-DA fluorescent probe, and Western blot. RESULTS: ATP and P2X4 were upregulated in EMS. Apyrase or 5-BDBD treatment or P2X4 knockdown reduced the concentration of Ca2+ and levels of IL-1β, TNF-α, IL-6, MDA, and ROS, but increased the activities of SOD, GSH-Px, and CAT in eESCs. Besides, 5-BDBD treatment decreased the expression levels of the NLRP3 inflammasome pathway-related proteins in eESCs and suppressed the secretion of IL-1β and IL-18. Nigericin could reverse the inhibitory impact of 5-BDBD on NLRP3 inflammasome activation. CONCLUSION: Altogether, ATP/P2X4 aggravates inflammation and oxidative stress in EMS by activating NLRP3.
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Abstract

Purpose Endometriosis (EMS) is a chronic inflammatory disorder with ectopic endometrial tissues arising in extrauterine areas. We investigated the mechanism of adenosine triphosphate (ATP)/P2X4 regulating inflammation and oxidative stress in EMS.

Methods

Normal endometrial tissues and ectopic endometrial tissues were collected, and determined for P2X4 expression by immunohistochemical staining. Normal (nESCs) and ectopic endometrial stromal cells (eESCs) were isolated and manipulated with Apyrase (a soluble ATP-diphosphohydrolase), 5-BDBD (a P2X4 receptor antagonist), or Nigericin (a NOD-like receptor 3 [NLRP3] inflammasome activator). The ATP concentration in endometrial tissues and cells were assessed through the ATP colorimetric/fluorescence assay, and cellular P2X4 expression was determined by RT-qPCR. Fluo 3-AM calcium ion fluorescence probe was utilized for detecting calcium ion concentration. Levels of inflammation-associated proteins (interleukin [IL]-1β, tumor necrosis factor-alpha [TNF-α], IL-6, IL-18), oxidative stress indicators (malondialdehyde [MDA], superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GSH-Px]), reactive oxygen species (ROS), and the NLRP3 inflammasome pathway-related proteins were determined by ELISA, DCFH-DA fluorescent probe, and Western blot.

Results

ATP and P2X4 were upregulated in EMS. Apyrase or 5-BDBD treatment or P2X4 knockdown reduced the concentration of Ca2+ and levels of IL-1β, TNF-α, IL-6, MDA, and ROS, but increased the activities of SOD, GSH-Px, and CAT in eESCs. Besides, 5-BDBD treatment decreased the expression levels of the NLRP3 inflammasome pathway-related proteins in eESCs and suppressed the secretion of IL-1β and IL-18. Nigericin could reverse the inhibitory impact of 5-BDBD on NLRP3 inflammasome activation.

Conclusion

Altogether, ATP/P2X4 aggravates inflammation and oxidative stress in EMS by activating NLRP3. Conflicts of Interest The authors declare no conflicts of interests. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Condition tags

endometriosis

MeSH descriptors

Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate Adenosine Triphosphate

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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