title: High glucose and hyperglycemic sera from type 2 diabetic patients impair DC differentiation by inducing ROS and activating Wnt/β-catenin and p38 MAPK.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Maria Saveria
authors.initials: MS
authors.lastname: Gilardini Montani
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Granato
authors.affiliation: U.O.C. Patologia Clinica, A.C.O. San Filippo Neri, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cuomo
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Valia
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Di Renzo
authors.affiliation: Department of Translational Oncology, Regina Elena National Cancer Institute, Rome, Italy; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", 66013, Chieti, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy. Electronic address: alberto.faggioni@uniroma1.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Faggioni
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy. Electronic address: mara.cirone@uniroma1.it.
authors.forename: Mara
authors.initials: M
authors.lastname: Cirone
mesh_terms: D001786:Blood Glucose; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology*; D044967:Serum; D060449:Wnt Signaling Pathway / Q000276:immunology*; D051176:beta Catenin / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology*
chemical_list: D001786:Blood Glucose; D017382:Reactive Oxygen Species; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: DC; Hyperglycemia; Quercetin; ROS; Wnt/β-catenin; p38 MAPK