Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium.
Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium.
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DOI：
10.1371/journal.pone.0151416
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Sheldon IM
中科院分区：
文献类型：
--
作者：
Turner ML;Cronin JG;Noleto PG;Sheldon IM
当代谢能量应激时，对通常感染产后牛子宫内膜的细菌的防御系统会受到损害，导致子宫内膜炎和不孕。子宫内膜对细菌的反应依赖于先天免疫，识别病原体相关的分子模式刺激炎症，其特征是分泌白介素1β、白介素6和白介素8。新陈代谢应激如何影响组织对病原体的反应尚不清楚，但能量代谢和先天免疫的整合意味着，对一个系统的压力可能会影响另一个系统。在这里，我们测试了牛子宫内膜组织中内环境平衡途径整合能量代谢和先天免疫的假设。在病原菌相关分子模式脂多糖和细菌脂多肽的刺激下，缺糖使牛子宫内膜体外器官培养物中IL-1β、IL-6和IL-8的分泌减少。激活或抑制细胞内能量感受器AMP激活的蛋白激酶(AMPK)的小分子也可以减少内毒素引起的子宫内膜炎性反应。然而，雷帕霉素是一种比AMPK更具全球性的代谢感受器，对哺乳动物靶点的抑制对炎症几乎没有影响。同样，子宫内膜炎性反应不受胰岛素样生长因子-1的影响，胰岛素样生长因子-1是新陈代谢的内分泌调节因子。有趣的是，对脂多糖的炎症反应增加了子宫内膜的葡萄糖消耗，并诱导了Warburg效应，这可能会加剧组织中葡萄糖供应的不足。总之，代谢能量应激扰乱了牛子宫内膜组织对病原体相关分子模式的炎症反应，而细胞能量的最基本调节因子葡萄糖可获得性和AMPK对先天免疫的影响最大。
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.