title: The oxidative stress product carboxyethylpyrrole potentiates TLR2/TLR1 inflammatory signaling in macrophages.
abstract: Oxidative stress is key in the pathogenesis of several diseases including age-related macular degeneration (AMD), atherosclerosis, diabetes, and Alzheimer's disease. It has previously been established that a lipid peroxidation product, carboxyethylpyrrole (CEP), accumulates in the retinas of AMD patients. Retinal infiltrating macrophages also accumulate in the retinas of both AMD patients and in a murine model of AMD. We therefore investigated the ability of CEP-adducts to activate innate immune signaling in murine bone-marrow derived macrophages (BMDMs). We found that CEP specifically synergizes with low-dose TLR2-agonists (but not agonists for other TLRs) to induce production of inflammatory cytokines. Moreover, CEP selectively augments TLR2/TLR1-signaling instead of TLR2/TLR6-signaling. These studies uncover a novel synergistic inflammatory relationship between an endogenously produced oxidation molecule and a pathogen-derived product, which may have implications in the AMD disease process and other oxidative stress-driven pathologies.
authors.affiliation: Sheila and David Fuente Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Ali M
authors.initials: AM
authors.lastname: Saeed
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Duffort
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Ivanov
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Laird
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Salomon
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cruz-Guilloty
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Perez
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051194:Toll-Like Receptor 1 / Q000096:biosynthesis* / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis* / Q000235:genetics; D051216:Toll-Like Receptor 6 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D011758:Pyrroles; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6