Abstract
BackgroundDespite being one of the major causes of infertility in mares, the mechanisms responsible for equine endometrosis are still unclear and controversial. In the last few years, many investigations focused on local immune response modulation. Since it is generally accepted that endometrial fibrosis increases with age, we hypothesize that older mares could show altered local immune modulation, initiating a pro-inflammatory and tissue remodeling cascade of events that could lead to endometrosis. The aim of this study, indeed, is to evaluate and describe the local gene expression of genes involved in acute inflammatory response and fibrosis (COL1A1, COL3A1, TNFA, MMP9, IL6, TGFB1 and TGFBR1), together with others associated to immune modulation (DEFB4B, IDO1 and FOXP3), in uterine specimens from mares of different age.ResultsTwenty-five Standardbred mares were involved in the study with age ranging from 7 to 19 years (mean 10.40 ± 4.42). They were divided by age into two groups: G1 (n = 15, less than 10 years old) and G2 (N = 10, greater than 11 years old). Specimens from the uterus’ right horn-body junction were collected and processed for histology evaluation and RT-qPCR assay.Gene expression of DEFB4B, MMP9 and TNFA was higher in younger mares, suggesting a balance in immune modulation and tissue remodeling. Interleukin-6 and COL3A1 gene expressions were greater in older animals, probably indicating inflammatory pathways activation and fibrosis increase. Although no differences in fibrosis and inflammation distribution could be found with histological examination among G1 and G2, our results suggest a possible involvement of DEF4BB in regulating the local immune response in younger mare’s uterus (G1); age may contribute to the dis-regulation of DEFB4B transcription and, indirectly, influence the extracellular matrix homeostasis. Transcription of IDO1 and FOXP3 genes, instead, does not seem to be age related, or to be involved in local immune-response and tissue remodeling functions.ConclusionsFurther investigations are needed in order to clarify the interactions between the expression of DEFB4B, IL6, TNFA, COL3A1 and MMP9 and other local signals of immune-modulation and tissue remodeling, in mares in a prospective study design.
Highlights
Despite being one of the major causes of infertility in mares, the mechanisms responsible for equine endometrosis are still unclear and controversial
Studies based on Crociati et al BMC Veterinary Research (2019) 15:465 immunohistochemistry and RT-qPCR revealed that the synthesis of pro-inflammatory mediators, such as interleukin-1α (IL1α), interleukin-1β (IL1β), interleukin6 (IL6), interleukin-10 (IL10) and tumor necrosis factorα (TNFA), alters the production of transforming growth factor-β (TGF-β), tissue inhibitor of metalloproteinase-1 (TIMP-1) and type-I collagen (COL1), inducing periglandular fibrosis [3, 4, 9, 10]
Recent studies hypothesize that modulation of the local immune response plays a role in the development of endometrial fibrosis [21]; a group of genes involved in the modulation of the immune response and in the activation of the innate immune-system are β-defensins (DEFB), which expression has been characterized by Johnson et al [12] in equine reproductive tract but independently on age or endometrosis degree
Summary
Despite being one of the major causes of infertility in mares, the mechanisms responsible for equine endometrosis are still unclear and controversial. Since it is generally accepted that endometrial fibrosis increases with age, we hypothesize that older mares could show altered local immune modulation, initiating a pro-inflammatory and tissue remodeling cascade of events that could lead to endometrosis. Kenney [5] introduced histological classification to grade endometrosis in mares, which is considered a proxy of pregnancy maintaining probability. Despite this association, mechanisms responsible for endometrial modifications are still unclear [3, 6]. Equine species shows physiological breeding-induced endometritis, which is an acute phenomenon; due to this characteristics, some Authors suggested that repeated endometrial immunechallenge, acute inflammation and alteration of the endometrial healing process could increase the risk of chronic inflammation, facilitating collagen deposition and endometrosis [9,10,11]
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