Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.
Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.
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DOI：
10.1016/j.cmet.2012.05.009
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发表时间：
2012-07-03
期刊：
影响因子：
29
通讯作者：
Hotamisligil GS
中科院分区：
文献类型：
--
作者：
ten Freyhaus H;Calay ES;Yalcin A;Vallerie SN;Yang L;Calay ZZ;Saatcioglu F;Hotamisligil GS
六跨膜蛋白Stamp2在新陈代谢引发的炎症和胰岛素作用中发挥重要作用。然而，Stamp2如何以及在哪些靶细胞中调节炎症反应及其生理后果仍不清楚。在此，我们报道了Stamp2在人和小鼠巨噬细胞中的表达，受分化或激活的调节，作为一种抗炎蛋白，并调节泡沫细胞的形成。Stamp2的缺失导致细胞内NADPH水平显著增加，并且NADPH的稳态和Stamp2−/−巨噬细胞夸大的炎症反应都可以被外源野生型拯救，但不是由还原酶缺陷的Stamp2分子拯救。化学和遗传抑制Stamp2−/−巨噬细胞中NADPH的产生可以恢复增强的炎症反应。Stamp2在小鼠和人的动脉粥样硬化斑块中都有检测到，它的缺失会促进小鼠的动脉粥样硬化。此外，骨髓移植实验证明，髓系细胞中的Stamp2足以保护动脉粥样硬化。我们的数据揭示了Stamp2在控制中间代谢产物以调节巨噬细胞的炎症反应和动脉粥样硬化进展中的作用。
The six-transmembrane protein Stamp2 plays an important role in metabolically-triggered inflammation and insulin action. However, how and in which target cells Stamp2 regulates inflammatory responses and the physiological consequences remain unknown. Here we report that Stamp2 is expressed in human and mouse macrophages, is regulated upon differentiation or activation, acts as an anti-inflammatory protein, and regulates foam cell formation. Absence of Stamp2 results in significant increases in cellular NADPH levels, and both NADPH homeostasis and the exaggerated inflammatory response of Stamp2−/− macrophages are rescued by exogenous wild-type but not by a reductase-deficient Stamp2 molecule. Chemical and genetic suppression of NADPH production in Stamp2−/− macrophages restores the heightened inflammatory response. Stamp2 is detected in mouse and human atherosclerotic plaques and its deficiency promotes atherosclerosis in mice. Furthermore, bone marrow transplantation experiments demonstrated that Stamp2 in myeloid cells is sufficient to protect against atherosclerosis. Our data reveal a role of Stamp2 in controlling intermediary metabolites to regulate inflammatory responses in macrophages and in progression of atherosclerosis.
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