Endometritis and endometrial fibrosis are associated with alterations in mare endometrial proteome

Equine persistent post-breeding endometritis may lead to endometrosis, characterized by excessive fibrosis, which is a major cause of subfertility/infertility. Endometrial proteomic changes induced by endometritis, when associated with fibrosis, were investigated to identify the biological processes (BP) involved. Cyclic mares´ endometrial biopsies were histologically classified (Kenney and Doig's) as: category IIA (n = 5), category IIA with endometritis (IIA-E; n = 4), category IIB (n = 5), or category IIB with endometritis (IIB-E; n = 5). Proteome was assessed by LC-MS/MS. In total, 62 differentially abundant proteins (DAPs) were identified in IIA-E endometria, compared to IIA; and 46 in IIB-E endometria, compared to IIB. The DAPs in endometria with endometritis (IIA-E vs. IIA; IIB-E vs. IIB) were mostly enriched in BP related to immune/inflammatory response, DNA-related process and cell cycle. Inflammatory-related proteins (serpin proteins and several phospholipases) were upregulated in endometritis, regardless of the degree of fibrosis and inflammation, suggesting the activation of conserved innate immune mechanisms. Nevertheless, fibrosis severity determined the expression pattern of histone H2A, which was upregulated in IIA-E endometria, and downregulated in IIB-E endometria. Additionally, other inflammatory-related proteins (azurocidin 1, eosinophil peroxidase and secreted phosphoprotein 1) were differently abundant only in endometritis associated with endometrosis (IIB-E), indicating that moderate fibrosis and endometrial degeneration may influence the inflammatory and tissue remodelling response. In conclusion, although conserved innate immune mechanisms operate independently of fibrosis severity and of endometrial inflammatory state, other processes activated during endometritis are influenced by the endometrium milieu, namely by the progression of endometrial fibrosis, which might modulate specific molecular responses.