Gilardini Montani Maria Saveria, Granato Marisa, Cuomo Laura, Valia Sandro, Di Renzo Livia, D'Orazi Gabriella, Faggioni Alberto, Cirone Mara
Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy.
U.O.C. Patologia Clinica, A.C.O. San Filippo Neri, Rome, Italy.
Biochim Biophys Acta. 2016 Apr;1862(4):805-813. doi: 10.1016/j.bbadis.2016.01.001. Epub 2016 Jan 6.
Type 2 is the type of diabetes with higher prevalence in contemporary time, representing about 90% of the global cases of diabetes. In the course of diabetes, several complications can occur, mostly due to hyperglycemia and increased reactive oxygen species (ROS) production. One of them is represented by an increased susceptibility to microbial infections and by a reduced capacity to clear them. Therefore, knowing the impact of hyperglycemia on immune system functionality is of utmost importance for the management of the disease. In this study, we show that medium containing high glucose reduced the in-vitro differentiation of monocytes into functional DCs and their activation mediated by PAMPs or DAMPs. Most importantly, the same effects were mediated by the hyperglycemic sera derived by type 2 diabetic patients, mimicking a more physiologic condition. DC dysfunction caused by hyperglycemia may be involved in the inefficient control of infections observed in diabetic patients, given the pivotal role of these cells in both the innate and adaptive immune response. Searching for the molecular mechanisms underlying DC dysfunction, we found that canonical Wnt/β-catenin and p38 MAPK pathways were activated in the DCs differentiated either in the presence of high glucose or of hyper-glycemic sera. Interestingly, the activation of these pathways and the DC immune dysfunction were partially counteracted by the anti-oxidant quercetin, a flavonoid already known to exert several beneficial effects in diabetes.
2型糖尿病是当代患病率较高的糖尿病类型，约占全球糖尿病病例的90%。在糖尿病病程中，可能会出现多种并发症，主要是由于高血糖和活性氧（ROS）生成增加所致。其中之一表现为对微生物感染的易感性增加以及清除感染的能力降低。因此，了解高血糖对免疫系统功能的影响对于该疾病的管理至关重要。在本研究中，我们发现含高糖的培养基会降低单核细胞体外分化为功能性树突状细胞（DCs）的能力及其由病原体相关分子模式（PAMPs）或损伤相关分子模式（DAMPs）介导的激活。最重要的是，2型糖尿病患者的高血糖血清也介导了相同的效应，更模拟了生理状态。鉴于这些细胞在固有免疫和适应性免疫反应中的关键作用，高血糖引起的DC功能障碍可能与糖尿病患者中观察到的感染控制不佳有关。在寻找DC功能障碍潜在的分子机制时，我们发现经典的Wnt/β-连环蛋白和p38丝裂原活化蛋白激酶（MAPK）信号通路在高糖或高血糖血清存在下分化的DCs中被激活。有趣的是，抗氧化剂槲皮素部分抵消了这些信号通路的激活以及DC免疫功能障碍，槲皮素是一种已知在糖尿病中发挥多种有益作用的类黄酮。
