title: Metal ions potentiate microglia responsiveness to endotoxin.
abstract: Oral metal exposure has been associated with diverse adverse reactions, including neurotoxicity. We showed previously that dentally applied metals activate dendritic cells (MoDC) via TLR4 (Ni, Co, Pd) and TLR3 (Au). It is still unknown whether the low levels of dental metals reaching the brain can trigger local innate cells or prime them to become more responsive. Here we tested whether dentally applied metals (Cr, Fe, Co, Ni, Cu, Zn, Au, Hg) activate primary human microglia in vitro and, as a model, monocytic THP-1-cells, in high non-toxic as well as near-physiological concentrations. In addition the effects of 'near-physiological' metal exposure on endotoxin (LPS) responsiveness of these cells were evaluated. IL-8 and IL-6 production after 24h was used as read out. In high, non-toxic concentrations all transition metals except Cr induced IL-8 and IL-6 production in microglia, with Ni and Co providing the strongest stimulation. When using near-physiological doses (up to 10× the normal plasma concentration), only Zn and Cu induced significant IL-8 production. Of note, the latter metals also markedly potentiated LPS responsiveness of microglia and THP-1 cells. In conclusion, transition metals activate microglia similar to MoDCs. In near-physiological concentrations Zn and Cu are the most effective mediators of innate immune activation. A clear synergism between innate responses to Zn/Cu and LPS was observed, shedding new light on the possible relation between oral metal exposure and neurotoxicity.
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands; Dept. of Biomedical Science, Faculty of Dentistry, University of Jember, Indonesia. Electronic address: d.rachmawati@unej.ac.id.
authors: Dessy
authors: D
authors: Rachmawati
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Laura A N
authors: LA
authors: Peferoen
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands; Neuroimmunology Unit Department of Molecular Cell Biology Immunology, VU University, Amsterdam, The Netherlands.
authors: Daphne Y S
authors: DY
authors: Vogel
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Inás W A
authors: IW
authors: Alsalem
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands; Neuroimmunology, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK.
authors: Sandra
authors: S
authors: Amor
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Hetty J
authors: HJ
authors: Bontkes
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: B Mary E
authors: BM
authors: von Blomberg
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Rik J
authors: RJ
authors: Scheper
authors: Dept. of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. Electronic address: i.vanhoogstraten@vumc.nl.
authors: Ingrid M W
authors: IM
authors: van Hoogstraten
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001921:Brain / Q000473:pathology*; D001927:Brain Diseases / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008670:Metals / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D008875:Middle Aged
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008670:Metals
keywords: Dentally applied metals; Innate immune activation; Microglia; Neurotoxicity; THP-1