Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.
Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
Front Immunol. 2018 Nov 15;9:2646. doi: 10.3389/fimmu.2018.02646. eCollection 2018.
Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Prevention of type 1 diabetes requires early intervention in the autoimmune process against beta-cells of the pancreatic islets of Langerhans, which is believed to result from disordered immunoregulation. CD4Foxp3 regulatory T cells (Tregs) participate as one of the most important cell types in limiting the autoimmune process. The aim of this study was to investigate the effect of exogenous IL-33 in multiple low dose streptozotocin (MLD-STZ) induced diabetes and to delineate its role in the induction of protective Tregs in an autoimmune attack. C57BL/6 mice were treated i. p. with five doses of 40 mg/kg STZ and 0.4 μg rIL-33 four times, starting from day 0, 6, or 12 every second day from the day of disease induction. 16 weeks old NOD mice were treated with 6 injections of 0.4 μg/mouse IL-33 (every second day). Glycemia and glycosuria were measured and histological parameters in pancreatic islets were evaluated at the end of experiments. Cellular make up of the pancreatic lymph nodes and islets were evaluated by flow cytometry. IL-33 given simultaneously with the application of STZ completely prevented the development of hyperglycemia, glycosuria and profoundly attenuated mononuclear cell infiltration. IL-33 treatment was accompanied by higher number of IL-13 and IL-5 producing CD4 T cells and increased presence of ST2Foxp3 regulatory T cells in pancreatic lymph nodes and islets. Elimination of Tregs abrogated protective effect of IL-33. We provide evidence that exogenous IL-33 completely prevents the development of T cell mediated inflammation in pancreatic islets and consecutive development of diabetes in C57BL/6 mice by facilitating the induction Treg cells. To extend this finding for possible relevance in spontaneous diabetes, we showed that IL-33 attenuate insulitis in prediabetic NOD mice.
1 型糖尿病是一种由胰腺β细胞的免疫介导破坏引起的自身免疫性疾病。1 型糖尿病的预防需要早期干预胰岛朗格汉斯岛的β细胞的自身免疫过程，这被认为是由于免疫调节紊乱引起的。CD4Foxp3 调节性 T 细胞（Tregs）作为限制自身免疫过程的最重要细胞类型之一参与其中。本研究旨在探讨外源性 IL-33 在多次低剂量链脲佐菌素（MLD-STZ）诱导的糖尿病中的作用，并阐明其在自身免疫攻击中诱导保护性 Tregs 的作用。C57BL/6 小鼠腹腔注射 5 次 40mg/kg STZ 和 0.4μg rIL-33，从疾病诱导的第 0、6 或 12 天开始，每隔一天 4 次。16 周龄 NOD 小鼠用 6 次 0.4μg/只 IL-33（每隔一天）处理。在实验结束时测量血糖和尿糖，并评估胰岛的组织学参数。通过流式细胞术评估胰腺淋巴结和胰岛的细胞组成。IL-33 与 STZ 同时给药可完全防止高血糖、糖尿和单核细胞浸润的发生。IL-33 治疗伴随着更多的 IL-13 和 IL-5 产生的 CD4 T 细胞和增加 ST2Foxp3 调节性 T 细胞在胰腺淋巴结和胰岛中的存在。Treg 细胞的消除消除了 IL-33 的保护作用。我们提供的证据表明，外源性 IL-33 通过促进 Treg 细胞的诱导，完全防止了 C57BL/6 小鼠胰岛中 T 细胞介导的炎症的发展和随后的糖尿病的发展。为了将这一发现扩展到自发性糖尿病的可能相关性，我们表明 IL-33 减轻了 NOD 小鼠的胰岛炎。
