Deactivation of the NLRP3 inflammasome in infiltrating macrophages by duodenal-jejunal bypass surgery mediates improvement of beta cell function in type 2 diabetes
Deactivation of the NLRP3 inflammasome in infiltrating macrophages by duodenal-jejunal bypass surgery mediates improvement of beta cell function in type 2 diabetes
复制标题
十二指肠空肠绕道手术使浸润巨噬细胞中的 NLRP3 炎症小体失活可改善 2 型糖尿病中的 β 细胞功能
DOI：
10.1016/j.metabol.2017.10.015
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发表时间：
2018-04-01
影响因子：
9.8
通讯作者：
Hu, San-yuan
中科院分区：
文献类型：
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作者：
Wu, Dong;Yan, Zhi-bo;Hu, San-yuan
目标。减肥手术可以改善胰腺β细胞功能，从而导致2型糖尿病（T2DM）的缓解。然而，这一现象背后的具体机制尚不清楚。本研究旨在验证浸润性巨噬细胞中含有nod样受体家族pyrin结构域3 （NLRP3）炎症小体在十二指肠-空肠旁路（DJB）手术后β细胞功能调节中发挥重要作用的假设。采用高脂饮食（HFD）和链脲佐菌素（STZ）诱导的糖尿病大鼠进行DJB和假手术治疗。在指定时间点测量体重、食物摄入量和葡萄糖耐量试验（GTT）。采用末端脱氧核苷酸转移酶介导的dUTP尼克末端标记法（TUNEL）检测β细胞的凋亡情况。我们还评估了巨噬细胞含量和NLRP3在大鼠模型中的表达。此外，DJB术后进行巨噬细胞重建。野生型巨噬细胞重构组和NLRP3敲低型巨噬细胞重构组重测β细胞功能和NLRP3炎性体通路。DJB手术组大鼠的葡萄糖耐量表现出快速和持续的改善。DJB手术组细胞凋亡减少，β细胞分泌功能改善。浸润性巨噬细胞NLRP3炎性体通路在DJB手术后也受到抑制。此外，DJB获得的糖尿病缓解在nlrp3敲除巨噬细胞重构组中持续，而在野生型巨噬细胞重构组中消失。
Objective. Bariatric surgery could improve pancreatic beta cell function, thereby leading to the remission of the type 2 diabetes mellitus (T2DM). However, the specific mechanism underlying this phenomenon is yet to be revealed. The aim of this study is to test the hypothesis that Nod-like receptor family pyrin domain containing3 (NLRP3) inflammasome in infiltrating macrophages plays an important role in the modulation of beta cell function after duodenal-jejunal bypass (DJB) surgery.Methods. DJB and sham surgery were performed in diabetic Sprague-Dawley (SD) rats induced by high-fat diet (HFD) and streptozotocin (STZ). Body weight, food intake, and glucose tolerance test (GTT) were measured at indicated time points. Apoptosis of the beta cells was measured by Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) assay. We also assessed the macrophage content and NLRP3 expression in the rat model. Furtheremore, macrophage reconstitution was performed afrer DJB surgery. Beta cell function and NLRP3 inflammasome pathway were re-evaluated in wild-type macrophage reconstitution group and NLRP3-knockdown macrophage reconstitution group.Results. DJB Surgery group rats displayed rapid and sustained improvement in glucose tolerance. Decreased apoptosis and improved secretion function of the beta cells were observed in DJB surgery group. NLRP3 inflammasome pathway in infiltrating macrophages was also suppressed after DJB surgery. Moreover, diabetic remission acquired by DJB sustained in NLRP3-knockdown macrophage reconstitution group, while extinguished in group reconstituted with wild-type macrophage.