Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia.
Front Immunol. 2019 Jan 10;9:3130. doi: 10.3389/fimmu.2018.03130. eCollection 2018.
Type 1 diabetes (T1D) is an autoimmune disease in which a strong inflammatory response causes the death of insulin-producing pancreatic β-cells, while inefficient regulatory mechanisms allow that response to become chronic. Ethyl pyruvate (EP), a stable pyruvate derivate and certified inhibitor of an alarmin-high mobility group box 1 (HMGB1), exerts anti-oxidant and anti-inflammatory properties in animal models of rheumatoid arthritis and encephalomyelitis. To test its therapeutic potential in T1D, EP was administered intraperitoneally to C57BL/6 mice with multiple low-dose streptozotocin (MLDS)-induced T1D. EP treatment decreased T1D incidence, reduced the infiltration of cells into the pancreatic islets and preserved β-cell function. Apart from reducing HMGB1 expression, EP treatment successfully interfered with the inflammatory response within the local pancreatic lymph nodes and in the pancreas. Its effect was restricted to boosting the regulatory arm of the immune response through up-regulation of tolerogenic dendritic cells (CD11cCD11bCD103) within the pancreatic infiltrates and through the enhancement of regulatory T cell (Treg) levels (CD4CD25FoxP3). These EP-stimulated Treg displayed enhanced suppressive capacity reflected in increased levels of CTLA-4, secreted TGF-β, and IL-10 and in the more efficient inhibition of effector T cell proliferation compared to Treg from diabetic animals. Higher levels of Treg were a result of increased differentiation and proliferation (Ki67 cells), but also of the heightened potency for migration due to increased expression of adhesion molecules (CD11a and CD62L) and CXCR3 chemokine receptor. Treg isolated from EP-treated mice had the activated phenotype and T-bet expression more frequently, suggesting that they readily suppressed IFN-γ-producing cells. The effect of EP on Treg was also reproduced . Overall, our results show that EP treatment reduced T1D incidence in C57BL/6 mice predominantly by enhancing Treg differentiation, proliferation, their suppressive capacity, and recruitment into the pancreas.
1 型糖尿病（T1D）是一种自身免疫性疾病，其中强烈的炎症反应导致产生胰岛素的胰腺β细胞死亡，而低效的调节机制使该反应变为慢性。丙酮酸乙酯（EP）是一种稳定的丙酮酸衍生物，是高迁移率族蛋白 1（HMGB1）警报素的抑制剂，在类风湿关节炎和脑脊髓炎的动物模型中具有抗氧化和抗炎作用。为了测试其在 T1D 中的治疗潜力，EP 被腹腔内给予多发性低剂量链脲佐菌素（MLDS）诱导的 T1D C57BL/6 小鼠。EP 治疗降低了 T1D 的发生率，减少了细胞浸润到胰岛并保留了β细胞功能。除了降低 HMGB1 表达外，EP 治疗还成功地干扰了局部胰腺淋巴结和胰腺内的炎症反应。其作用仅限于通过上调胰腺浸润物中的耐受性树突状细胞（CD11cCD11bCD103）和增强调节性 T 细胞（Treg）水平（CD4CD25FoxP3）来增强免疫反应的调节臂。这些 EP 刺激的 Treg 显示出增强的抑制能力，表现在更高水平的 CTLA-4、分泌的 TGF-β 和 IL-10 以及更有效地抑制效应 T 细胞增殖，与来自糖尿病动物的 Treg 相比。Treg 水平升高是由于分化和增殖（Ki67 细胞）增加所致，但由于黏附分子（CD11a 和 CD62L）和 CXCR3 趋化因子受体表达增加而导致迁移能力增强也是如此。从 EP 治疗的小鼠中分离出的 Treg 具有激活表型和 T-bet 表达更频繁，这表明它们容易抑制 IFN-γ 产生细胞。EP 对 Treg 的作用也得到了重现。总体而言，我们的结果表明，EP 治疗通过增强 Treg 的分化、增殖、抑制能力和招募到胰腺中，降低了 C57BL/6 小鼠 T1D 的发生率。
