M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling.
M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling.
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作者：
Lee WJ;Tateya S;Cheng AM;Rizzo-DeLeon N;Wang NF;Handa P;Wilson CL;Clowes AW;Sweet IR;Bomsztyk K;Schwartz MW;Kim F
内皮一氧化氮（NO）信号在限制肥胖相关的胰岛素抵抗和炎症中发挥生理作用。本研究进行调查是否这种NO效应涉及极化的巨噬细胞向抗炎M2表型。转基因内皮型NO合酶过表达的小鼠可免受高脂饮食（HFD）诱导的肝脏炎症和胰岛素抵抗的影响，这种作用与枯否细胞的促炎性M1减少和抗炎性M2激活增加有关。在细胞培养研究中，巨噬细胞暴露于内皮NO类似地减少炎症（M1）和增加抗炎（M2）基因表达。巨噬细胞过度表达血管舒张刺激磷蛋白（VASP），细胞内NO信号传导的关键下游介质诱导类似的效果。相反，VASP缺乏诱导促炎性M1巨噬细胞活化，并且将VASP缺乏的供体小鼠的骨髓移植到正常受体中引起肝脏炎症和胰岛素抵抗，类似于在正常小鼠中通过消耗HFD诱导的肝脏炎症和胰岛素抵抗。这些数据表明，促炎性巨噬细胞M1活化和巨噬细胞介导的炎症受到NO → VASP信号转导的紧张性抑制，并且减少的NO → VASP信号转导参与了HFD喂养诱导枯否细胞M1活化和相关肝脏炎症的作用。我们的数据暗示内皮NO → VASP信号传导是巨噬细胞极化的生理决定因素，并表明通过该途径的信号传导是预防肝脏炎症和胰岛素抵抗所必需的。
Endothelial nitric oxide (NO) signaling plays a physiological role in limiting obesity-associated insulin resistance and inflammation. This study was undertaken to investigate whether this NO effect involves polarization of macrophages toward an anti-inflammatory M2 phenotype. Mice with transgenic endothelial NO synthase overexpression were protected against high-fat diet (HFD)-induced hepatic inflammation and insulin resistance, and this effect was associated with reduced proinflammatory M1 and increased anti-inflammatory M2 activation of Kupffer cells. In cell culture studies, exposure of macrophages to endothelial NO similarly reduced inflammatory (M1) and increased anti-inflammatory (M2) gene expression. Similar effects were induced by macrophage overexpression of vasodilator-stimulated phosphoprotein (VASP), a key downstream mediator of intracellular NO signaling. Conversely, VASP deficiency induced proinflammatory M1 macrophage activation, and the transplantation of bone marrow from VASP-deficient donor mice into normal recipients caused hepatic inflammation and insulin resistance resembling that induced in normal mice by consumption of an HFD. These data suggest that proinflammatory macrophage M1 activation and macrophage-mediated inflammation are tonically inhibited by NO → VASP signal transduction, and that reduced NO → VASP signaling is involved in the effect of HFD feeding to induce M1 activation of Kupffer cells and associated hepatic inflammation. Our data implicate endothelial NO → VASP signaling as a physiological determinant of macrophage polarization and show that signaling via this pathway is required to prevent hepatic inflammation and insulin resistance.