Hyperglycemia in Stroke Impairs Polarization of Monocytes/Macrophages to a Protective Noninflammatory Cell Type
Hyperglycemia in Stroke Impairs Polarization of Monocytes/Macrophages to a Protective Noninflammatory Cell Type
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DOI：
10.1523/jneurosci.0473-16.2016
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发表时间：
2016-09-07
影响因子：
5.3
通讯作者：
Schwaninger, Markus
中科院分区：
文献类型：
--
作者：
Khan, Mahtab A.;Schultz, Sina;Schwaninger, Markus
高血糖是急性中风患者的常见症状，即使在那些没有糖尿病的患者中也是如此，并预示着不良结局。然而，高血糖有害影响的潜在机制在很大程度上尚不清楚。在一种缺血性中风的小鼠模型中，我们发现高血糖增加了脑梗塞的体积，并减少了脑内保护性非炎症性单核/巨噬细胞的数量。外周血单核细胞消融可阻断高血糖的不利影响，提示单核细胞是必需的。在高血糖小鼠中，晚期糖基化终末产物的前体--α-二羰基葡萄糖代谢物在血浆和脑缺血组织中显著升高。晚期糖基化终末产物受体AGE(以前称为RAGE)干扰巨噬细胞向非炎症性表型的极化。删除AGER后，高血糖不再加重缺血性脑损伤。与AGE无关的是，甲乙二醛减少了内皮CSF-1(M-CSF)的释放，后者刺激巨噬细胞极化为缺血脑微环境中的非炎症性表型。综上所述，我们的研究确定了α-二羰基和AGE是高血糖降低保护性非炎症性巨噬细胞数量从而增加缺血性脑损伤的介质。调节α-二羰基代谢或阻断AGE可改善高血糖卒中患者的治疗。
Hyperglycemia iscommonin patients with acute stroke, even in those without preexisting diabetes, and denotes a bad outcome. However, the mechanisms underlying the detrimental effects of hyperglycemia are largely unclear. In a mouse model of ischemic stroke, we found that hyperglycemia increased the infarct volume and decreased the number of protective noninflammatory monocytes/macrophages in the ischemic brain. Ablation of peripheral monocytes blocked the detrimental effect of hyperglycemia, suggesting that monocytes are required. In hyperglycemic mice, alpha-dicarbonyl glucose metabolites, the precursors for advanced glycation end products, were significantly elevated in plasma and ischemic brain tissue. The receptor of advanced glycation end products, AGER (previously known as RAGE), interfered with polarization of macrophages to a noninflammatory phenotype. When Ager was deleted, hyperglycemia did not aggravate ischemic brain damage any longer. Independently of AGER, methylglyoxal reduced the release of endothelial CSF-1 (M-CSF), which stimulates polarization of macrophages to a noninflammatory phenotype in the microenvironment of the ischemic brain. In summary, our study identified alpha-dicarbonyls and AGER as mediators by which hyperglycemia lowers the number of protective noninflammatory macrophages and consequently increases ischemic brain damage. Modulating the metabolism of alpha-dicarbonyls or blocking AGER may improve the treatment of stroke patients with hyperglycemia.