Postbiotics for NOD2 require nonhematopoietic RIPK2 to improve blood glucose and metabolic inflammation in mice
Postbiotics for NOD2 require nonhematopoietic RIPK2 to improve blood glucose and metabolic inflammation in mice
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DOI：
10.1152/ajpendo.00033.2020
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发表时间：
2020-04-01
影响因子：
5.1
通讯作者：
Schertzer, Jonathan D.
中科院分区：
文献类型：
--
作者：
Cavallari, Joseph F.;Barra, Nicole G.;Schertzer, Jonathan D.
确定宿主受体和细菌成分的代谢后果可以帮助解释微生物组如何影响代谢性疾病。细菌肽聚糖激活核苷酸结合寡聚结构域（NOD）1会使葡萄糖控制恶化，而NOD2激活会改善血糖。受体相互作用丝氨酸/苏氨酸蛋白激酶2 （RIPK2）是由NOD1和NOD2诱导的先天免疫所必需的。RIPK2在NOD1与NOD2对血糖的不同作用中的作用尚不清楚。我们发现，在小鼠急性、低水平内毒素攻击期间，RIPK2的全身缺失可消除NOD1或NOD2激活对血糖的所有影响。已知造血细胞中的NOD1参与肥胖小鼠的胰岛素抵抗和代谢性炎症。目前尚不清楚造血细胞中的RIPK2是否需要激活NOD2的降血糖和抗炎作用。我们假设非造血细胞中的RIPK2决定了NOD2激活的血糖效应。我们发现，在高脂肪饮食（HFD）喂养的野生型（WT）小鼠的葡萄糖耐量试验（GTT）中，RIPK2的全身缺失阻止了NOD2重复激活的降血糖作用。在造血细胞中RIPK2缺失的小鼠中，NOD2激活降低了GTT期间的葡萄糖和脂肪组织炎症。我们得出结论，非造血细胞中的RIPK2介导nod2激活后生物制剂的降血糖和抗炎作用。我们提出了一个模型，其中脂多糖和NOD1配体在造血细胞中协同促进胰岛素抵抗，而NOD2在非造血细胞中的激活促进ripk2依赖性免疫耐受和降低炎症和胰岛素抵抗。
Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2. The role of RIPK2 in the divergent effects of NOD1 versus NOD2 on blood glucose was unknown. We found that whole body deletion of RIPK2 negated all effects of NOD1 or NOD2 activation on blood glucose during an acute, low level endotoxin challenge in mice. It was known that NOD1 in hematopoietic cells participates in insulin resistance and metabolic inflammation in obese mice. It was unknown if RIPK2 in hematopoietic cells is required for the glucose-lowering and anti-inflammatory effects of NOD2 activation. We hypothesized that RIPK2 in nonhematopoietic cells dictated the glycemic effects of NOD2 activation. We found that whole body deletion of RIPK2 prevented the glucose-lowering effects of repeated NOD2 activation that were evident during a glucose tolerance test (GTT) in high-fat diet (HFD)-fed wild-type (WT) mice. NOD2 activation lowered glucose during a GTT and lowered adipose tissue inflammation in mice with RIPK2 deleted in hematopoietic cells. We conclude that RIPK2 in nonhematopoietic cells mediates the glucose lowering and anti-inflammatory effects of NOD2-activating postbiotics. We propose a model where lipopolysaccharides and NOD1 ligands synergize in hematopoietic cells to promote insulin resistance but NOD2 activation in nonhematopoietic cells promotes RIPK2-dependent immune tolerance and lowering of inflammation and insulin resistance.