Oxidized Low Density Lipoprotein Immune Complexes Prime the NLRP3 Inflammasome and Modulate T cell Responses in Atherosclerosis

Abstract

Oxidized low-density lipoprotein (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells. Much of the oxLDL in circulation is complexed to antibodies, and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory diseases including atherosclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Levels of oxLDL-ICs often correlate with disease severity; however, it was previously unknown how oxLDL-ICs modulate immune responses. This work demonstrates that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL-ICs secrete significantly more IL-1β compared with BMDCs treated with free oxLDL, and treatment of BMDCs with oxLDL-ICs increased expression of inflammasome-related genes. This inflammasome priming was due to oxLDL-IC signaling via multiple receptors, and signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 complex. Injection of oxLDL-ICs into LDLr-/- mice enhanced atherosclerotic lesion size and caused aortic dissection which may promote lesion instability. Finally, oxLDL IC-mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data show that oxLDL-ICs induce potent and unique innate and adaptive immune responses.