Immune and Extracellular Matrix Dynamics in Chronic Endometritis: Insights into Endometrial Homeostasis and Fibrogenic Niche Evolution

ORIGINAL ARTICLE
S. A. Mikhalev, M.A. Kurtser, V.E. Radzinsky, Narasimha M. Beeraka, A.A. Kostin, D.A. Atiakshin, M.R. Orazov, L.M. Mikhaleva

 
For citation: Mikhalev SA, Kurtser MA, Radzinsky VE, Beeraka NM, Kostin AA, Atiakshin DA, Orazov MR, Mikhaleva LM. Immune and Extracellular Matrix Dynamics in Chronic Endometritis: Insights into Endometrial Homeostasis and Fibrogenic Niche Evolution. International Journal of Biomedicine. 2025;15(1):119-128. doi:10.21103/Article15(1)_OA11
 
Originally published March 5, 2025

Abstract: 

Background: Chronic endometritis (CE), a condition involving abnormal immune responses in the endometrial microenvironment, is associated with infertility and implantation failure. Yet, the underlying regulatory mechanisms of autoimmunity and tissue homeostasis are not fully understood. Identifying molecular and biological markers that characterize the pathogenesis and morphogenesis of CE could help predict disease progression and risk. This study aims to explore the molecular and biological underpinnings of CE across varying levels of severity.
Methods and Results: This prospective observational comparative study included 53 women of reproductive age with abnormal uterine bleeding and a history of RPL. All women were presented with CE, which was histologically verified. Endometrial samples were obtained via Pipelle biopsy using a Pipelle vacuum syringe during the mid-proliferative phase (days 7-10 of the menstrual cycle). The biopsies underwent pathomorphological analysis following modified Noyes criteria for CE confirmation. Based on CE severity, participants were categorized into three groups: Group 1 (mild inflammation), Group 2 (moderate inflammation), and Group 3 (severe inflammation).
In our study, mild CE was characterized by an adaptive immune response, with increased CD8+T-cell density and overexpression of CD38+, CD68+, and CD163+. Collagen-producing cell activity was moderately elevated, accompanied by a relative increase in reticular fibers. In moderate CE, the microenvironment displayed a reactive immune response, evidenced by overexpression of pro-inflammatory markers CD38+ and CD68+, alongside impaired fibrillogenesis. Macrophage activity shifted toward an M2 anti-inflammatory response with higher CD163+ expression. In severe CE, severe inflammation correlated with an upregulated expression and cooperative interaction of pro-inflammatory markers (CD8+, CD68+, CD38+) and an abundance of type III collagen-rich reticular fibers against a backdrop of mitigated CD163+ expression. This advanced severity suggested a decline in anti-inflammatory regulation and an excessive deposition of ECM components.
Conclusion: The findings show that CE severity is modulated by a complex interplay of immune and cellular factors, typically with progressive ECM fibrous formation and collagen and reticular fiber ratio shifts. The severity of inflammation aligns with elevated pro-inflammatory factors (CD8+, CD68+, and CD38+) and reduced anti-inflammatory CD163+ expression, particularly in severe CE. These molecular and cellular insights elucidate the significance of biomarkers for diagnosing and stratifying CE severity, providing a basis for targeted interventions to mitigate CE progression.

Keywords: 
chronic endometritis • immune microenvironment • collagen metabolism • inflammatory markers • endometrial dysfunction • extracellular matrix
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Received November 11, 2024.
Accepted January 1, 2025.
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