Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
Nat Metab. 2024 Nov;6(11):2082-2099. doi: 10.1038/s42255-024-01159-9. Epub 2024 Nov 4.
Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain in both sexes are prone to stalling, with blocks consisting primarily of erythrocytes in branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstruction, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice reversed these impairments. Chronic treatment of diabetic mice with IL-10 receptor neutralizing antibodies improved cerebral blood flow, increased capillary flux and diameter, downregulated haemostasis and cell adhesion-related gene expression, and reversed cognitive deficits. These data suggest that IL-10 signalling has an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment associated with type 1 diabetes.
血管病理学与 1 型糖尿病等疾病的认知障碍有关；然而，毛细血管的流动如何受到影响以及潜在的机制仍不清楚。在这里，我们发现在雄性和雌性糖尿病小鼠的大脑中，毛细血管很容易停滞，上升的小静脉分支中的阻塞物主要由红细胞组成。对循环炎症细胞因子的筛选显示，糖尿病小鼠中白细胞介素 10（IL-10）的水平持续升高。与预期相反，刺激 IL-10 信号增加了毛细血管阻塞，而用中和抗体抑制糖尿病小鼠的 IL-10 受体或内皮细胞特异性敲低则逆转了这些损伤。用 IL-10 受体中和抗体对糖尿病小鼠进行慢性治疗可改善脑血流，增加毛细血管通量和直径，下调止血和细胞黏附相关基因表达，并逆转认知缺陷。这些数据表明，IL-10 信号在与 1 型糖尿病相关的大脑微循环缺陷和认知障碍中具有意想不到的致病作用。
