Modulation of the immune system during post-partum uterine infection
Post-partum uterine infection is associated with lower fertility at both the time of infection and after the infection has resolved. The objective of this study was to characterize genome-wide DNA methylation and gene expression in the endometrium of dairy cows with sub-clinical endometritis. It was hypothesized that aberrant DNA methylation may be involved in the sub-fertility associated with post-partum uterine infection. Endometrial tissues were obtained at 29 days post-partum (n=12) and Agilent two-colour microarrays were used to characterize transcription and DNA methylation profiles. Analyses revealed 1,856 probes to be differentially expressed in animals with subclinical endometritis (SUI) compared with control cows (P<0.05, Storey Multiple testing correction). No significant associations among DNA methylation and gene expression were detected. Further analysis using GeneGo Metacore and Gene Set Enrichment Analysis identified several pathways and processes enriched in the comparison. Several pathways that are involved in the innate immune response were enriched in SUI cows. Consistent with activation of toll like receptors (TLR) by microorganisms present in the uterus, there was enrichment for the TLR signaling pathway including increased expression of the transcription factor NFKB1, the pro-inflammatory cytokines IL1A and IL1B, downstream chemokines, cytokines, and acute phase and antimicrobial proteins in the endometrium of SUI cows. Further, the chemokine signaling pathway was enriched in SUI cows, with increased expression of genes that attract cells of the innate immune system. Increased expression of IL-8 and CXCL6, chemotactic factors for recruitment of neutrophils along with the immune cell surface marker PTPRC in SUI cows is consistent with the greater number of polymorphonuclear cells present in the uterus of these cows. Several antimicrobial peptides (LAP, TAP, DEFB1, DEFB10, DEFB103B, DEFB7) and acute phase proteins including SAA3, LBP and the complement gene CFB had greater expression in SUI cows. Gene expression profiles in cows with subclinical endometritis in this study indicate that the immune response is activated, potentially resulting in a local pro-inflammatory environment in the uterus. If this period of inflammation is prolonged it could result in tissue damage or failure to complete involution of the uterus that may create a sub-optimal environment for future pregnancy.