Adaptor Protein-3–Mediated Trafficking of TLR2 Ligands Controls Specificity of Inflammatory Responses but Not Adaptor Complex Assembly
| Autor: | Aurelie Kern, Tess L. Killpack, Linden T. Hu, Tanja Petnicki-Ocwieja, Stephen C. Bunnell |
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| Rok vydání: | 2015 |
| Předmět: |
Cell signaling
Adaptor Protein Complex 3 Immunology Biology Article Lipopeptides Mice L Cells Immune system Phagosomes Animals Immunology and Allergy Borrelia burgdorferi Cells Cultured Phagosome Mice Knockout Mice Inbred C3H Membrane Glycoproteins Microscopy Confocal Innate immune system Macrophages Receptors Interleukin-1 Signal transducing adaptor protein Receptors Interleukin biology.organism_classification Toll-Like Receptor 2 Cell biology Mice Inbred C57BL Protein Transport TLR2 Host-Pathogen Interactions Myeloid Differentiation Factor 88 Cytokines Inflammation Mediators Lysosomes |
| Zdroj: | The Journal of Immunology. 195:4331-4340 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1501268 |
| Popis: | Innate immune engagement results in the activation of host defenses that produce microbe-specific inflammatory responses. A long-standing interest in the field of innate immunity is to understand how varied host responses are generated through the signaling of just a limited number of receptors. Recently, intracellular trafficking and compartmental partitioning have been identified as mechanisms that provide signaling specificity for receptors by regulating signaling platform assembly. We show that cytokine activation as a result of TLR2 stimulation occurs at different intracellular locations and is mediated by the phagosomal trafficking molecule adaptor protein-3 (AP-3). AP-3 is required for trafficking TLR2 purified ligands or the Lyme disease causing bacterium, Borrelia burgdorferi, to LAMP-1 lysosomal compartments. The presence of AP-3 is necessary for the activation of cytokines such as IL-6 but not TNF-α or type I IFNs, suggesting induction of these cytokines occurs from a different compartment. Lack of AP-3 does not interfere with the recruitment of TLR signaling adaptors TRAM and MyD88 to the phagosome, indicating that the TLR-MyD88 signaling complex is assembled at a prelysosomal stage and that IL-6 activation depends on proper localization of signaling molecules downstream of MyD88. Finally, infection of AP-3–deficient mice with B. burgdorferi resulted in altered joint inflammation during murine Lyme arthritis. Our studies further elucidate the effects of phagosomal trafficking on tailoring immune responses in vitro and in vivo. |
| Databáze: | OpenAIRE |
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