From the Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan.
From the Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan,
J Biol Chem. 2018 Apr 20;293(16):5934-5946. doi: 10.1074/jbc.M117.809228. Epub 2018 Mar 1.
Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic β cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked β-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives β-cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent β-cell loss in patients with diabetes.
在 2 型糖尿病患者的胰岛中观察到慢性低度炎症，并且这些个体的胰岛中巨噬细胞水平升高。然而，胰岛β细胞与巨噬细胞之间相互作用的分子机制及其在炎症中的作用尚不完全清楚。在这里，我们研究了 S100 钙结合蛋白 A8（S100A8），一种损伤相关分子模式分子（DAMPs）成员，在β细胞炎症中的作用。在棕榈酸（诱导脂肪毒性）和高葡萄糖（诱导糖毒性）存在下，将胰岛与未刺激的腹腔巨噬细胞共培养以协同方式非依赖性地增加胰岛产生的 S100A8 的表达和释放。一致地，在糖尿病 db/db 小鼠的胰岛中观察到基因的显著增加。此外，胰岛衍生的 S100A8 诱导迁移巨噬细胞中 TLR4 介导的炎性细胞因子产生。当人胰岛细胞与人单核细胞 U937 共培养时，棕榈酸处理上调 S100A8 表达。这种胰岛和巨噬细胞之间的 S100A8 介导的相互作用引发β细胞凋亡，而巨噬细胞中的 TLR4 抑制或胰岛中的 S100A8 中和可减轻这种凋亡。值得注意的是，糖毒性和脂肪毒性均从胰岛中触发 S100A8 的分泌，这反过来又促进巨噬细胞浸润胰岛。总之，胰岛衍生的 S100A8 和巨噬细胞之间的正反馈环驱动β细胞凋亡和胰腺胰岛炎症。我们得出结论，开发抑制 S100A8 的治疗方法可能有助于防止糖尿病患者的β细胞损失。
