Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes.
Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes.
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DOI：
10.4049/jimmunol.1601543
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发表时间：
2017-01-15
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影响因子：
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通讯作者：
Van Dyke TE
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作者：
Freire MO;Dalli J;Serhan CN;Van Dyke TE
未解决的炎症是2型糖尿病中代谢失调和免疫系统联系的关键。急性炎症的成功调节需要专门的促消退脂质介质（如消退素E1（RvE 1））的生物合成和同源g蛋白偶联受体（GPCR）的激活。RvE 1与中性粒细胞上的BLT-1和单核细胞/巨噬细胞上的ERV-1/ChemR 23结合。我们显示新的行动RvE 1和中性粒细胞受体的表达模式在2型糖尿病。来自健康受试者的中性粒细胞表达功能性BLT-1，低水平的最低功能性ERV-1和2型糖尿病中的反向共表达。用TNFα或LPS刺激增加健康和糖尿病中性粒细胞ERV-1的表达。RvE 1可抵消LPS和TNFα诱导的ERV 1过表达和糖尿病过表达，激活吞噬和消退信号。通过信号蛋白核糖体S6（rS6）的磷酸化来确定ERV-1的功能。受体拮抗实验表明，磷酸-rS6的增加是由BLT-1在健康受试者中性粒细胞和ERV 1在糖尿病介导的。金属脂质组学揭示了糖尿病血清中的促炎特征。2型糖尿病患者的细胞吞噬功能受损，需要RvE 1激活。在2型糖尿病中性粒细胞中激活分辨率信号所需的RvE 1剂量显著高于健康对照组。RvE 1挽救了异常的中性粒细胞受体谱，并在治疗剂量后激活吞噬作用和2型糖尿病的消退。这些发现揭示了分辨率受体在2型糖尿病的健康，疾病和炎症失调中的重要性。
Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized pro-resolving lipid mediators, such as resolvin E1 (RvE1), and activation of cognate g-protein coupled receptors (GPCR). RvE1 binds to BLT-1 on neutrophils and ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1 and inversed co-expression in type2 diabetes. Stimulation with TNFα or LPS increased expression of ERV-1 by healthy and diabetic neutrophils. RvE1 has counteracted LPS and TNFα induction of ERV1 overexpression and diabetic overexpression activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein, ribosomal S6 (rS6). Receptor antagonism experiments revealed that the phospho-rS6 increase was mediated by BLT-1 in healthy subject neutrophils and ERV1 in diabetes. Metalolipidomics reveal a pro-inflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than healthy controls. RvE1 rescued aberrant neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease and dysregulation of inflammation in type 2 diabetes.