Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium

Abstract

Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity.

Postpartum uterine infection and endometritis in dairy cattle

“…In addition, vaccines containing components of E. coli, F. necrophorum and/or T. pyogenes protect animals against postpartum uterine disease (Nolte et al, 2001;Machado et al, 2014). However, metagenomics techniques have found associations between uterine disease and bacteria that are not readily cultured by standard techniques (Machado et al, 2012;Santos and Bicalho, 2012;Peng et al, 2013;Knudsen et al, 2015;Wagener et al, 2015). Whilst some of the studies find E. coli, T. pyogenes and the expected anaerobic bacteria, others report finding Bacteroidetes and Firmicutes.…”

“…Activation of the inflammasome typically leads to cleavage of pro-IL-1β and secretion of the mature form of IL-1β (Lamkanfi and Dixit, 2014). The Toll-like receptor system is present and active in the cells of the endometrium, both epithelium and stroma, as well as in bovine hematopoietic cells (Herath et al, 2006;Cronin et al, 2012Cronin et al, , 2016Turner et al, 2014). However, endometrial cells secrete little IL-1β protein, and so inflammasome activity may be more important in hematopoietic cells.…”

“…A series of checks and balances are in place to scale inflammation to meet the level of microbial threat, and to limit inflammation when infections are cleared (Blander and Sander, 2012). One example in the bovine endometrium, is the role of STAT3 to regulate the secretion of IL-6 and IL-8 in stromal cells (Cronin et al, 2016). Another example is the apical secretion of IL-6 and IL-8 from bovine endometrial epithelial cells, toward the invading pathogens in the uterine lumen and away from the underlying stromal cells (Healy et al, 2015).…”

“…Negative energy balance may impair the inflammatory response and clearance of bacteria from the endometrium, leading to chronic endometritis (Esposito et al, 2014). Certainly, the response to pathogen molecules is energetically expensive in vivo and in vitro (Turner et al, 2016;Kvidera et al, 2017). A striking example is that animals use >1 kg of glucose in the first 12 h after challenge with LPS (Kvidera et al, 2017).…”

“…A striking example is that animals use >1 kg of glucose in the first 12 h after challenge with LPS (Kvidera et al, 2017). Furthermore, the depletion of the key cellular nutrients, glucose or glutamine, reduces inflammatory responses by endometrial tissues in vitro (Turner et al, 2016;Noleto et al, 2017). If metabolic stress compromises the ability of animals to respond sufficiently to pathogens, this may result in persistence of infections and chronic inflammation.…”