Interleukin 17A in the fibrotic-related processes in endometrosis in the mare.

Overview

• This study investigates the role of interleukin 17A (IL-17A) in the fibrotic processes associated with equine endometrosis, a chronic degenerative uterine condition characterized by fibrosis in mares.
• The research focuses on analyzing IL-17A signaling components and their effects on cellular behavior, gene expression, extracellular matrix remodeling, and prostaglandin signaling in endometrial fibroblasts from healthy and fibrotic tissue.

Background and Purpose

• Equine Endometrosis: A chronic degenerative condition of the mare’s endometrium marked by progressive fibrosis that impairs uterine function and fertility.
• Interleukin 17A (IL-17A): A cytokine known to play a critical role in inflammation and fibrosis in various tissue types, but its role in equine endometrosis had not been elucidated.
• Objectives:
  • To determine the expression levels of IL-17A signaling components in equine endometrium with and without endometrosis.
  • To analyze how IL-17A influences gene expression profiles, cellular functions, and extracellular matrix (ECM) related factors in endometrial fibroblasts from both normal and fibrotic tissue.
  • To evaluate IL-17A’s impact on components of prostaglandin (PG) signaling, which can influence inflammation and tissue remodeling.

Methods

• Tissue Collection: Endometrial samples from mares with diagnosed endometrosis and from healthy controls were collected.
• Protein Analysis: Measurement of IL-17 receptor subunit A abundance was performed to compare levels between normal and fibrotic tissue.
• RNA-Sequencing: Performed on fibroblasts derived from both types of endometrium after IL-17A treatment to identify gene expression changes.
• Functional Assays: Assessed:
  • Fibroblast cellular functional characteristics and immunomodulatory properties.
  • Expression and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which regulate ECM remodeling.
  • Influence on prostaglandin signaling pathways.

Key Findings

• IL-17 Receptor Expression: The IL-17 receptor subunit A was significantly upregulated in endometrial tissue affected by endometrosis compared to healthy tissue, indicating enhanced sensitivity to IL-17A in fibrotic tissue.
• Differential Gene Expression:
  • In fibroblasts derived from healthy endometrium, IL-17A predominantly influenced genes associated with monocyte chemotaxis and macrophage activation, suggesting a role in initiating immune cell recruitment and activation.
  • In fibroblasts from endometrotic tissue, IL-17A affected genes linked to neutrophil activation and migration, possibly reflecting a shift toward neutrophil-driven inflammation in fibrosis.
• ECM Regulation: IL-17A modulated both the expression and enzymatic activity of MMPs and TIMPs in fibroblasts regardless of tissue origin, indicating a regulatory role in the balance between extracellular matrix deposition and degradation.
• Immunomodulatory Effects: IL-17A altered the immunomodulatory properties of equine endometrial fibroblasts differently depending on whether they originated from healthy or fibrotic tissue, highlighting context-dependent effects.

Significance and Implications

• Insights into Fibrosis Mechanisms: This study reveals that IL-17A signaling is intricately involved in the pathophysiology of endometrosis, affecting immune cell recruitment and ECM remodeling which are central to fibrosis progression.
• Potential Therapeutic Target: The upregulation of IL-17 receptor components and IL-17A’s influence on fibroblast behavior suggest that targeting IL-17 signaling might be a viable strategy to modulate fibrosis and improve uterine health in mares.
• Differential Responses: The distinct responses in fibroblasts from healthy versus diseased tissue emphasize the importance of tissue context when considering interventions aimed at IL-17 pathways.