Impaired Expression of Ectonucleotidases in Ectopic and Eutopic Endometrial Tissue Is in Favor of ATP Accumulation in the Tissue Microenvironment in Endometriosis

Abstract

Endometriosis is a prevalent disease defined by the presence of endometrial tissue outside the uterus. Adenosine triphosphate (ATP), as a proinflammatory molecule, promotes and helps maintain the inflammatory state of endometriosis. Moreover, ATP has a direct influence on the two main symptoms of endometriosis: infertility and pain. Purinergic signaling, the group of biological responses to extracellular nucleotides such as ATP and nucleosides such as adenosine, is involved in the biology of reproduction and is impaired in pathologies with an inflammatory component such as endometriosis. We have previously demonstrated that ectonucleotidases, the enzymes regulating extracellular ATP levels, are active in non-pathological endometria, with hormone-dependent changes in expression throughout the cycle. In the present study we have focused on the expression of ectonucleotidases by means of immunohistochemistry and in situ activity in eutopic and ectopic endometrial tissue of women with endometriosis, and we compared the results with endometria of women without the disease. We have demonstrated that the axis CD39-CD73 is altered in endometriosis, with loss of CD39 and CD73 expression in deep infiltrating endometriosis, the most severe, and most recurring, endometriosis subtype. Our results indicate that this altered expression of ectonucleotidases in endometriosis boosts ATP accumulation in the tissue microenvironment. An important finding is the identification of the nucleotide pyrophophatase/phosphodiesterase 3 (NPP3) as a new histopathological marker of the disease since we have demonstrated its expression in the stroma only in endometriosis, in both eutopic and ectopic tissue. Therefore, targeting the proteins directly involved in ATP breakdown could be an appropriate approach to consider in the treatment of endometriosis.

Prospects for the Treatment of Endometriosis: The Effect of Immune Peptides on the Reactivation of Immune Surveillance over Ectopic Endometrial Cells

“…Despite the undoubted importance of determining markers of systemic changes in immunity, it is believed that the main role in the pathogenesis of external forms of GE is still the local interaction of the components of the immune system and pathologically altered cells, therefore, the activity of local factors, in particular macrophages of the peritoneal fluid, is of particular importance. Regression or progression of foci of external GE is caused by the interaction of macrophages with stromal endometrial cells with subsequent synthesis of cytokines (interleukins, growth factors, interferons), which cause death or, conversely, increased proliferation of these cells [9][10][11][12][13]. [8].…”

Purinergic Signaling in Endometriosis-Associated Pain

“…NTPDase2, NTPDase3, NPP1, NPP3, ALP, CD26, and CD73 are expressed by endometrial epithelial cells, while NTPDase1, NTPDase2, and CD73 have been detected in endometrial stromal cells [ 26 ]. Although the ectonucleotidases studied to date are mainly present in the endometrial epithelium, most of the changes detected in endometriosis occur in the stroma [ 37 ].…”

“…Changes in eutopic endometrium of women with endometriosis in comparison with the endometrium of women without the pathology have been detected [ 26 , 37 ]. Moreover, differences between the different types of endometriotic lesions have been described [ 37 ]. One notable change in endometriosis is the expression of NPP3.…”

“…Several studies of NPP3 expression in endometrial tissue have localized the protein in epithelial cells, with changes along the cycle [ 26 , 38 , 39 ]. In endometriosis, however, NPP3 is found to be expressed by the stroma, as well as the epithelium, in both eutopic and ectopic endometrial tissues [ 37 ]. This de novo expression of NPP3 points to its use as a putative histopathological marker of the disease.…”

“…Moreover, the great decrease in, or even the total loss, of the CD39–CD73 axis in endometrial tissue in endometriosis further suggests that extracellular adenosine synthesis is rather limited. [ 37 ]. In fact, these data suggest a relation between extracellular ATP accumulation and the severity and progression of endometriosis, since the loss of CD39–CD73 is related to deep infiltrating endometriosis, the most severe form of the illness with high recurrence rates and a high level of associated pain [ 45 , 46 ].…”