Transcriptomic Insights into Tumor Necrosis Factor α's Role in the Fibrosis-Related Processes of Equine Endometrial Fibroblasts.

Abstract

Equine endometrosis is a chronic degenerative condition of the endometrium. A hallmark feature of endometrosis is endometrial fibrosis accompanied by degenerative changes in the adjacent tissue structure. Tumor necrosis factor &#x3b1; (TNF&#x3b1;), a pleiotropic cytokine produced by various immune cells, plays a dual role in coordinating immune responses and regulating cell/tissue homeostasis, making it an important regulator of fibrotic-related disorders. However, the exact role of TNF&#x3b1; in the development of equine endometrial fibrosis remains to be discovered and explained. Therefore, the main aim of the current study was to establish the effects of TNF&#x3b1; on the equine endometrial fibroblast transcriptome as well as on proliferation and expression of ECM-associated factors incultured fibroblasts derived from non-fibrotic equine endometrium. RNA-sequencing revealed changes in the expression of 737 genes (p< 0.05; log2FC &#x2265; 1.0/log2FC &#x2264; -1.0) between untreated and TNF&#x3b1;-treated equine endometrial fibroblasts. These genes are involved in, i.a., B cell activation, proliferation and differentiation, cell cycle, canonical NF-&#x3ba;B signal transduction, ERK1 and ERK2 cascade, and p53 signaling pathway. Moreover, it was found that TNF&#x3b1; increased fibroblast proliferation and affected the expression of metalloproteinases and their tissue inhibitors in mare endometrial fibroblasts. Results of the current study highlight that TNF&#x3b1; modulates the expression of genes related to immune cell activation, cell fate, and ECM remodeling incultured equine endometrial fibroblasts, suggesting TNF&#x3b1; contribution in development of fibrosis in the mare endometrium. Since the current study provides mechanistic insight into TNF&#x3b1; action, these findings provide a foundation for future research aimed at targeting TNF&#x3b1;-mediated pathways as potential therapeutic strategies to mitigate equine endometrial fibrosis progression.