Abstract 152: Oxidized Low-Density Lipoprotein Immune Complexes Generate an Inflammatory Immune Response by Signaling Through Multiple Receptors on Dendritic Cells

Abstract

Antibodies to oxidized LDL (oxLDL) and resulting immune complexes (ICs) are a prominent feature of atherosclerosis and diseases associated with increased atherosclerosis including Type 2-diabetes and rheumatoid arthritis. Although levels of oxLDL-ICs correlate with disease severity and associate with pro-inflammatory activation of macrophages in vitro , it is currently unclear whether these ICs are simply biomarkers or play an active role in disease pathogenesis. One possible mechanism by which oxLDL-ICs may regulate inflammation in atherosclerosis is by interacting with Fc gamma receptors (FcgRs) expressed on the surface of antigen presenting cells, such as dendritic cells (DCs). Not surprisingly, signaling through FcgRs is tightly regulated and dependent on their relative cell surface density. In addition, FcgR signaling has been shown to be linked to Toll like receptor-4 (TLR-4), a pattern recognition receptor. We hypothesize that oxLDL-ICs exacerbate atherosclerosis via signaling through FcgRs and TLR4 on DCs resulting in a pro-inflammatory T cell response. To test this hypothesis, bone marrow derived DCs (BMDCs) were treated with in vitro generated oxLDL ICs. Interestingly, BMDCs treated with oxLDL-ICs had increased expression of the activation markers MHC-II and CD40 and produced greater levels of the Th17 polarizing cytokines IL-1beta and IL-23 compared to cells treated with oxLDL alone. Secretion of pro-inflammatory cytokines was significantly decreased by pre-treatment of BMDCs with a TLR4 inhibitor and by blocking FcgR signaling. This suggests that responses to oxLDL-ICs involve both TLR-4 and FcgRs. Furthermore, incubation of OT-II T cells with BMDCs treated with oxLDL-IC prior to incubation with ovalbumin peptide displayed increased pro-inflammatory cytokine secretion compared to incubation with oxLDL alone. In conclusion, our studies provide new evidence that oxLDL-ICs signal through multiple receptors on DCs resulting in increased inflammatory potential. Because of their critical function in shaping the T cell response, we believe that DC signaling via FcgRs and oxLDL-ICs represents an important link between innate and adaptive immunity in atherosclerosis.