Obesity is associated with inflammatory macrophages in insulin responsive tissues and the resulting inflammatory response is a major contributor to insulin resistance. In insulin-producing pancreatic islets, the intra-islet accumulation of macrophages is observed in patients of type 2 diabetes (T2D), but such has not been investigated in obese individuals. Here, we show that pro-inflammatory cytokines (IL-1β, IL-6, and TNF), anti-inflammatory cytokines (IL-10 and TGF-β) and macrophage polarization markers (CD11c, CD163, and NOS2) were expressed in isolated human islets from non-diabetic donors. Clodronate-mediated depletion of resident macrophages revealed expression of IL1B and IL10 mostly from macrophages, while IL6, TNF, and TGFB1 came largely from a non-macrophage origin in human islets. NOS2 expression came exclusively from non-macrophage cells in non-obese individuals, while it originated also from macrophages in obese donors. Macrophage marker expression of CD68, CD163, and ITGAX was unchanged in islets of non-obese control and obese cohorts. In contrast, IL1B and NOS2 were significantly increased in islets from obese, compared to non-obese individuals, implying a more inflammatory macrophage phenotype in islets in obesity. Our study shows elevated macrophage-associated inflammation in human islets in obesity, which could be an initiating factor to the pro-inflammatory intra-islet milieu and contribute to the higher susceptibility to T2D in obese individuals.

中文翻译：

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来自肥胖个体的人类胰岛中巨噬细胞相关的促炎状态。

肥胖与胰岛素反应组织中的炎性巨噬细胞有关，由此产生的炎症反应是胰岛素抵抗的主要原因。在产生胰岛素的胰岛中，在 2 型糖尿病 (T2D) 患者中观察到胰岛内巨噬细胞积聚，但尚未在肥胖个体中对此进行研究。在这里，我们显示促炎细胞因子（IL-1β、IL-6 和 TNF）、抗炎细胞因子（IL-10 和 TGF-β）和巨噬细胞极化标记物（CD11c、CD163 和 NOS2）在从非糖尿病捐赠者身上分离出人类胰岛。氯膦酸盐介导的常驻巨噬细胞耗竭显示 IL1B 和 IL10 的表达主要来自巨噬细胞，而 IL6、TNF 和 TGFB1 主要来自人类胰岛中的非巨噬细胞来源。NOS2 表达完全来自非肥胖个体的非巨噬细胞，而它也来自肥胖供体的巨噬细胞。CD68、CD163 和 ITGAX 的巨噬细胞标志物表达在非肥胖对照和肥胖人群的胰岛中没有变化。相比之下，与非肥胖个体相比，肥胖个体的胰岛中 IL1B 和 NOS2 显着增加，这意味着肥胖的胰岛中具有更多的炎症性巨噬细胞表型。我们的研究表明肥胖患者胰岛中巨噬细胞相关炎症升高，这可能是促炎性胰岛内环境的启动因素，并导致肥胖个体对 T2D 的易感性更高。ITGAX 在非肥胖对照和肥胖人群的胰岛中没有变化。相比之下，与非肥胖个体相比，肥胖个体的胰岛中 IL1B 和 NOS2 显着增加，这意味着肥胖的胰岛中具有更多的炎症性巨噬细胞表型。我们的研究表明肥胖患者胰岛中巨噬细胞相关炎症升高，这可能是促炎性胰岛内环境的启动因素，并导致肥胖个体对 T2D 的易感性更高。ITGAX 在非肥胖对照和肥胖人群的胰岛中没有变化。相比之下，与非肥胖个体相比，肥胖个体的胰岛中 IL1B 和 NOS2 显着增加，这意味着肥胖的胰岛中具有更多的炎症性巨噬细胞表型。我们的研究表明肥胖患者胰岛中巨噬细胞相关炎症升高，这可能是促炎性胰岛内环境的启动因素，并导致肥胖个体对 T2D 的易感性更高。