Symposium review: Mechanisms linking metabolic stress with innate immunity in the endometrium

Abstract

Bacterial infections of the uterus after parturition are ubiquitous in dairy cattle and often cause uterine disease, such as metritis or endometritis. However, the metabolic stress associated with milk production increases the risk of developing disease. Resolution of bacterial infections requires rapid and robust innate immune responses, which depend on host cell receptors recognizing pathogen-associated molecular patterns, such as lipopolysaccharide (LPS) from gram-negative bacteria. Here, we argue that metabolic stress impairs the inflammatory response to pathogens. Glucose and glutamine are the major energy sources for cells, but their abundance is reduced in postpartum dairy cows. Furthermore, inflammatory responses exacerbate metabolic stress, with animals and tissues consuming more glucose when challenged with LPS. However, depriving endometrial tissue of glucose or glutamine impairs the secretion of IL-1β, IL-6, and IL-8 in response to pathogen-associated molecular patterns. Glycolysis and the intracellular sensor of energy, AMP-activated protein kinase, are important for the response to LPS because perturbing glycolysis or AMP-activated protein kinase activity reduces the secretion of IL-1β, IL-6, and IL-8 in the endometrium. The mevalonate pathway for cellular cholesterol synthesis may also be linked to immunity, as inhibition of the terminal enzyme in the pathway, squalene synthase, reduces inflammatory responses to pathogenic bacteria and LPS. In contrast, only modest effects on inflammation are found when modulating the sensor of cellular nutrient satiety, mammalian target of rapamycin, or the endocrine regulator of metabolism, insulin-like growth factor-1. We suggest that stressing cellular metabolism increases the risk of uterine disease by impairing endometrial defenses.

Effect of anti-inflammatory treatment on systemic inflammation, immune function, and endometrial health in postpartum dairy cows

“…Lower biosynthesis of haptoglobin may improve hepatic metabolism of www.nature.com/scientificreports www.nature.com/scientificreports/ fatty acids. Glucose and IGF-1 concentrations are important markers of adaptation to NEB 53 . Therefore, our results validate a positive effect of meloxicam treatment on liver function and energy status of postpartum dairy cows, as indicated by decreased serum BHB concentrations and increased serum glucose.…”

“…Maladaptation to NEB in dairy cows is associated with a decline in PMN function [54][55][56] . PMN mainly depend on glucose for functions such as chemotaxis and bacterial killing 53,57,58 . High concentrations of NEFA, BHB, and haptoglobin are associated with decreased PMN function 25,27,59 .…”

Symposium review: Selection for fertility in the modern dairy cow—Current status and future direction for genetic selection

“…Postpartum uterine disease has long-term effects on the subsequent establishment of pregnancy (Carneiro et al, 2016;Ribeiro et al, 2016). The inability of the cow to resolve uterine disease may be explained in part by immune dysfunction early postpartum that is caused by a metabolic profile that antagonizes the innate immune system (Contreras et al, 2018;Sheldon et al, 2018).…”

“…The cow's immune system is primarily responsible for resolution of disease and recovery from inflammation within the uterus postpartum (Contreras et al, 2018;Sheldon et al, 2018). The low circulating glucose and elevated circulating BHB that are found during early lactation can antagonize circulating immune cell function (Lucy et al, 2014).…”

Transition Period of the Dairy Cow Revisited: II. Homeorhetic Stimulus and Ketosis With Implication for Fertility

“…Consequently, various aspects of the signal cascade from hypothalamus/pituitary, ovary, and uterus and from fetal development and (under)nutrition or metabolism have been studied and described: the dominant role of GnRH in the hypothalamus/pituitary and the release of gonadotropins (HPG axis) (Wade & Jones, 2004;Schneider, 2004;Clarke, 2014;Hill & Elias, 2018), the effects of nutrition and metabolic status on circulating hormones such as LH, FSH, estradiol, progesterone, insulin, and IGF-1 and possible effects on pre-ovulatory follicle growth and ovulation (Diskin et al, 2003, Wathes, 2012, the somatotropic axis and follicular growth (Silva et al, 2009;Lucy, 2012), the regulation of the corpus luteum (Wiltbank et al, 2012), the role of glucose for embryonic and fetal development (Lucy et al, 2014), progesterone and early pregnancy (Spencer et al, 2015), prostaglandins and maternal recognition (Arosh et al, 2016), oocyte development and stress (Roth, 2018), embryonic and early fetal loss (Diskin & Morris, 2008), the role of lipids as regulators of conceptus development (Ribeiro, 2018), and the interaction between metabolic stress and innate immunity and inflammation of the endometrium (Sheldon et al, 2017).…”