title: Immune complex formation in human diabetic retina enhances toxicity of oxidized LDL towards retinal capillary pericytes.
abstract: Recently it has been shown that levels of circulating oxidized LDL immune complexes (ox-LDL-ICs) predict the development of diabetic retinopathy (DR). This study aimed to investigate whether ox-LDL-ICs are actually present in the diabetic retina, and to define their effects on human retinal pericytes versus ox-LDL. In retinal sections from people with type 2 diabetes, costaining for ox-LDL and IgG was present, proportionate to DR severity, and detectable even in the absence of clinical DR. In contrast, no such staining was observed in retinas from nondiabetic subjects. In vitro, human retinal pericytes were treated with native LDL, ox-LDL, and ox-LDL-IC (0-200 mg protein/l), and measures of viability, receptor expression, apoptosis, endoplasmic reticulum (ER) and oxidative stresses, and cytokine secretion were evaluated. Ox-LDL-IC exhibited greater cytotoxicity than ox-LDL toward retinal pericytes. Acting through the scavenger (CD36) and IgG (CD64) receptors, low concentrations of ox-LDL-IC triggered apoptosis mediated by oxidative and ER stresses, and enhanced inflammatory cytokine secretion. The data suggest that IC formation in the diabetic retina enhances the injurious effects of ox-LDL. These findings offer new insights into pathogenic mechanisms of DR, and may lead to new preventive measures and treatments.
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Northern Ireland, UK.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Fu
authors.forename: Jeremy Y
authors.initials: JY
authors.lastname: Yu
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Wu
authors.forename: Mei
authors.initials: M
authors.lastname: Du
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Souzan A
authors.initials: SA
authors.lastname: Abdelsamie
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Li
authors.forename: Junping
authors.initials: J
authors.lastname: Chen
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.forename: Maria F
authors.initials: MF
authors.lastname: Lopes-Virella
authors.forename: Gabriel
authors.initials: G
authors.lastname: Virella
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lyons
mesh_terms: D000368:Aged; D000936:Antigen-Antibody Complex; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity*; D020286:Pericytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism; D012160:Retina / Q000503:physiopathology*
chemical_list: D000936:Antigen-Antibody Complex; D016207:Cytokines; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein
keywords: apoptosis; blood retinal barrier; diabetes; dyslipidemia; endoplasmic reticulum stress; immunohistochemistry; lipoprotein; oxidative stress; scavenger receptor