title: Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9.
abstract: Oxidized low-density lipoprotein (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells. Interestingly, much of the oxLDL in circulation is complexed to Abs, and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory disease, such as atherosclerosis, type-2 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Levels of oxLDL ICs often correlate with disease severity, and studies demonstrated that oxLDL ICs elicit potent inflammatory responses in macrophages. In this article, we show that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL ICs for 24 h secrete significantly more IL-1β compared with BMDCs treated with free oxLDL, whereas there was no difference in levels of TNF-α or IL-6. Treatment of BMDCs with oxLDL ICs increased expression of inflammasome-related genesIl1a,Il1b, andNlrp3, and pretreatment with a caspase 1 inhibitor decreased IL-1β secretion in response to oxLDL ICs. This inflammasome priming was due to oxLDL IC signaling via multiple receptors, because inhibition of CD36, TLR4, and FcγR significantly decreased IL-1β secretion in response to oxLDL ICs. Signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 signalosome complex involved in NF-κB translocation. Finally, oxLDL IC-mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data demonstrate that oxLDL ICs induce inflammasome activation through a separate and more robust mechanism than oxLDL alone and that these ICs may be immunomodulatory in chronic disease and not just biomarkers of severity.
authors.affiliation: Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN 37212.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Rhoads
authors.affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908.
authors.forename: John R
authors.initials: JR
authors.lastname: Lukens
authors.affiliation: Division of Rheumatology, Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Wilhelm
authors.affiliation: Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN 37212.|Division of Rheumatology, Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Moore
authors.affiliation: Department of Biology, Trevecca Nazarene University, Nashville, TN 37210; and.
authors.forename: Yanice
authors.initials: Y
authors.lastname: Mendez-Fernandez
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.affiliation: Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN 37212; amy.major@vanderbilt.edu.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232.|Division of Rheumatology, Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Major
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D058847:Inflammasomes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D020239:Receptor Cross-Talk; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017452:Receptors, IgG; D051193:Toll-Like Receptors