Oxidized low density lipoprotein immune complexes act as a priming signal for the NLRP3 inflammasome (HUM1P.253)

Abstract

Abstract Antibodies to oxidized LDL (oxLDL) and resulting immune complexes (ICs) are a prominent feature of atherosclerosis and autoimmune diseases associated with increased atherosclerosis. Although levels of oxLDL-ICs correlate with disease severity, it is unclear whether these ICs play an active role in disease pathogenesis. We hypothesize that oxLDL-ICs exacerbate atherosclerosis by signaling through multiple receptors on dendritic cells (DCs) resulting in an inflammatory adaptive immune response. To test this hypothesis, bone marrow derived dendritic cells (BMDC) were incubated with oxLDL or oxLDL-IC and cytokine levels in culture supernatants were measured by ELISA. Results indicated a 10-fold increase in IL-1β production from BMDC treated with oxLDL-IC compared to oxLDL, suggesting a role for the inflammasome in oxLDL-IC activation of DC. Pre-treatment of BMDC with a caspase 1 inhibitor and use of NLRP3-/- BMDC abolished IL-1β secretion in response to oxLDL-IC, further implicating the inflammasome. Additional investigation using Fab fragments and a TLR4 inhibitor uncovered a role for both FcγR and TLR4 in oxLDL-IC mediated IL-1β production. Finally, BMDC pre-treated with oxLDL-IC, but not oxLDL, and incubated with CD4+ OT-II T cells in the presence of OVA peptide skewed T cells towards a Th17 phenotype. Taken together, these data suggest a novel and pathologic role of oxLDL-ICs in activating the NLRP3 inflammasome and promoting an inflammatory T cell phenotype.