Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
J Clin Invest. 2012 Jan;122(1):132-41. doi: 10.1172/JCI46177. Epub 2011 Dec 19.
The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet β cell survival and HS degradation as a mechanism for β cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.
自发性发生在 NOD 小鼠中的自身免疫性 1 型糖尿病 (T1D) 被认为是人类 T1D 的模型。其特征是单核细胞 (MNC) 浸润胰岛，最终导致胰岛素产生的β细胞破坏。尽管 T 细胞依赖性，但触发β细胞死亡的分子机制尚未完全阐明。在这里，我们报告一种糖胺聚糖，硫酸乙酰肝素 (HS)，在小鼠胰岛中以极高的水平表达，对β细胞存活至关重要。在体外，β细胞迅速失去 HS 并死亡。HS 替代可预防β细胞死亡，该治疗还使β细胞对 ROS 损伤具有抗性。在体内，NOD 小鼠胰岛的自身免疫破坏与胰岛浸润的 MNC 产生具有催化活性的肝素酶有关，肝素酶是一种降解 HS 的酶，以及胰岛 HS 的丢失。此外，体内用肝素酶抑制剂 PI-88 治疗可保留胰岛内 HS，并可保护 NOD 小鼠免受 T1D 侵害。我们的研究结果确定 HS 是胰岛β细胞存活的关键分子需求，HS 降解是β细胞破坏的机制。我们的研究结果表明，保护胰岛 HS 可能是预防 T1D 的一种治疗策略。
