Tolerance and Innate Immunity Shape the Development of Postpartum Uterine Disease and the Impact of Endometritis in Dairy Cattle

Abstract

Bacteria are ubiquitous in the bovine uterus after parturition, but 50 years ago, cows tolerated these bacteria and few animals developed uterine disease. Now, up to 40% of dairy cattle develop postpartum uterine disease. Uterine disease causes infertility by compromising the function of not only the endometrium but also the ovary. Animals defend themselves against pathogens using tolerance and resistance mechanisms. Tolerance is the ability to limit the disease severity induced by a given pathogen burden. Resistance is the ability to limit the pathogen burden and is usually the function of immunity. Endometrial cells contribute to tolerance and have roles in innate immunity and the inflammatory response to pathogens. However, failures in endometrial tolerance and the character of the inflammatory response shape postpartum uterine disease. We propose that uterine health is more dependent on the ability of the endometrium to tolerate pathogens than the ability to resist invading bacteria.

Keywords: bovine; fertility; infection; inflammation; ovary; uterus.

Figure 1

Uterine disease is associated with impaired tolerance. (a) Cows with postpartum uterine disease discharge pus from the uterus. (b,c) Schematic reaction norms of health status against pathogen load for (b) two groups of animals with similar tolerance, where each animal is represented by a symbol (blue squares or orange circles), but the reaction norm for the blue group (blue line) indicates that these animals have impaired immunity, with reduced health status and more pathogens, compared with the orange group (orange line), or (c) two groups with similar immunity, but the reaction norm for the orange group (orange line) indicates that these animals are less tolerant, with reduced health at the same pathogen load as the blue group (blue line) [based on the concepts proposed by Raberg and others (–6)]. (d) Using data from a previously published study of postpartum uterine clinical health score and uterine bacterial load for dairy cows producing >35 L milk/day (orange circles, n = 56) and <35 L milk/day (blue squares, n = 34), the reaction norm for the cows producing >35 L milk/day (orange line) indicates that these metabolically stressed animals have impaired tolerance, with reduced health at the same pathogen load as the animals producing <35 L milk/day (blue line). Panel d adapted with permission from I.M. Sheldon.

Figure 2

Development of postpartum endometritis. ① After parturition, there is a bloom of bacterial growth in the uterus, and multiple pathogens compete with commensal bacteria in the endometrium. ② The mucus layer in the endometrium helps prevent bacteria from reaching the epithelium, and antimicrobial peptides (AMP) and acute phase proteins (APP) neutralize bacteria and their virulence factors. ③ Tight junctions between epithelial cells prevent bacteria penetrating to the underlying stroma, although, after parturition, epithelial cell damage exposes the stroma. ④ If bacteria reach the stroma, they often cause cell damage and cytolysis and provoke inflammatory responses, including the influx of neutrophils from the peripheral circulation.

Figure 3

The innate immune response in the endometrium. ① Endometrial epithelial (orange) and stromal (green) cells express functional Toll-like receptor 4 (TLR4) and TLR2/TLR1 and TLR2/TLR6 heterodimers. Binding of pathogen-associated molecular patterns to TLRs activates the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, which lead to the transcription of genes that encode several inflammatory mediators, including antimicrobial peptides (AMPs), cytokines, chemokines, and prostaglandins. Whereas most inflammatory mediators are released from cells into the extracellular fluid, in the polarized epithelial cells specific inflammatory mediators are secreted apically. ② Cells release the intracellular cytokine interleukin (IL)-1α (blue spheres) if cells are also damaged (lightning bolt). ③ In a paracrine manner, IL-1α can bind to the IL-1R of nearby cells, further activating the NF-κB and MAPK signaling pathways. ④ Epithelial and stromal cells respond differently to IL-6 (red spheres), and in stromal cells IL-6 has a positive feedback through the IL-6R/gp130 receptor heterodimer and signal transducer and activator of transcription-3 (STAT3) signaling to enhance the secretion of IL-6 and IL-8. Abbreviations: LPS, lipopolysaccharide; PGE₂, prostaglandin E₂.

Figure 4

Uterine disease affects ovarian function. ① Pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), and inflammatory mediators, such as cytokines and prostaglandin E₂ (PGE2), are abundant in the uterus of animals with postpartum endometritis. ② The PAMPs and inflammatory mediators reach the vasculature via the uterine vein and ③ then may reach the ovary by countercurrent mechanisms with the ovarian arterial circulation, local lymphatics, or the peripheral circulation. ④ PAMPs and inflammatory meditators perturb most of the stages of ovarian follicle and oocyte development, depicted in the ovary, ranging from primordial follicles to ovulation of the cumulus-oocyte complex (COC). Abbreviations: IL, interleukin; TNFα, tumor necrosis factor alpha.