Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells
| Autor: | Markus P. Radsak, Karl J. Lackner, Hansjörg Schild, Mareike Lorenz, Inge Pütz, Nadine Prinz, Dennis Strand, Adriana Degreif, Natascha Clemens, Pamela Stein, Philipp von Landenberg, Stefan Bauer, Andreas Daiber |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Endosome Immunology Endosomes In Vitro Techniques Biology Ligands medicine.disease_cause Biochemistry Monocytes Proinflammatory cytokine Autoimmunity Mice Superoxides immune system diseases medicine Animals Humans RNA Messenger Mice Knockout Autoimmune disease Membrane Glycoproteins Innate immune system Tumor Necrosis Factor-alpha Antibodies Monoclonal Interferon-alpha Dendritic Cells Cell Biology Hematology TLR7 TLR8 Antiphospholipid Syndrome medicine.disease Immunity Innate Cell biology Mice Inbred C57BL Protein Transport Toll-Like Receptor 7 Toll-Like Receptor 8 Antibodies Antiphospholipid Female Signal transduction Signal Transduction |
| Zdroj: | Blood. 118:2322-2332 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | The antiphospholipid syndrome (APS) is an autoimmune disease characterized by thromboembolic events and/or fetal loss in the presence of antiphospholipid antibodies (aPLs). The mechanisms underlying the pathogenicity of aPLs are still poorly understood. Here we show that 3 human monoclonal aPLs as well as IgG fractions from patients with the APS increase mRNA expression of the intracellular toll-like receptor (TLR) 7 in plasmacytoid dendritic cells and TLR8 in monocytes. Simultaneously they induce the translocation of TLR7 or TLR8 from the endoplasmic reticulum to the endosome. These effects depend on the uptake of aPLs into the endosome, subsequent activation of endosomal NADPH oxidase, and generation of superoxide. As a consequence cells are dramatically sensitized to ligands for TLR7 and TLR8. This observation delineates a novel signal transduction pathway in innate immunity originating from the endosome. Because the overexpression of TLR7 can also be detected in plasmacytoid dendritic cells from patients with the APS ex vivo, our results provide an explanation for proinflammatory and procoagulant effects of aPLs. Because inappropriate expression of TLR7 has been implicated in the development of systemic autoimmunity, these findings may also be relevant for the understanding of autoimmunity. |
| Databáze: | OpenAIRE |
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