oxLDL immune complex-mediated modulation of atherosclerosis



 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) accounts for the deaths of approximately 1 million Americans annually. Despite advances in modern medicine that have led to numerous treatment options, CVD has remained the leading cause of mortality in the US for over 80 years. Atherosclerosis, the most common form of CVD, is a disease of sterile inflammation characterized by accumulation of plaque in the arteries. It is thought that atherosclerosis is initiated by entry an sequestration of low density lipoproteins (LDL) in the vasculature where they subsequently become oxidized (oxLDL) and cause damage to local tissue. This results in the recruitment of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Following APC activation, an inflammatory cascade ensues, ultimately leading to an adaptive immune response and antibody production. While titers of antibodies to oxLDL and the resulting immune complexes (oxLDL-ICs) are known to correlate with disease severity, it is unknown if oxLDL-ICs play a role in disease pathogenesis. ICs can regulate inflammation in atherosclerosis by interacting with Fc gamma receptors (FcRs) expressed on the surface of DCs. Activating (FcRI/III) and inhibitory (FcRIIb) FcRs mediate opposing functions in DCs, shifting the balance between pro-inflammatory DC activation and tolerogenic responses. FcR signaling has been linked to Toll like receptor-4 (TLR-4), a pattern recognition receptor that can recognize free oxLDL. Furthermore, our preliminary data using a TLR-4 inhibitor suggest that oxLDL-ICs are able to signal through this receptor. Given that both oxLDL-ICs and DCs expressing TLR-4 have been observed in human atherosclerotic plaques, it is likely that oxLDL-IC signaling via the TLR-4 pathway and modulation of this pathway by FcRs are important in disease progression. Studies in macrophage cell lines have shown increased cellular activation following treatment with oxLDL-ICs. However, the role of DCs in this process is largely unstudied, and reports regarding the in vivo relevance are lacking. Given the potent ability of DCs to elicit a downstream immune response, understanding oxLDL-IC-mediated DC activation will fill a gap in our knowledge of CVD pathogenesis and provide new avenues for therapeutic intervention. Using both in vitro and in vivo models, the long term goal of this study is to provide a clear and comprehensive answer to this critical and long-standing question in the field of atherosclerosis. We hypothesize that 1) oxLDL-ICs augment TLR-4-mediated DC inflammatory responses leading to proatherogenic T cell differentiation and 2) the inhibitory FcRIIb protects against atherosclerosis by down-regulating DC inflammatory responses to oxLDL-ICs. To date, the effects of DC-specific FcRIIb signaling in atherosclerosis have not been examined. Being afforded the opportunity to test this hypothesis will allow us to make "big picture" conclusions regarding the role of oxLDL-ICs in CVD. Understanding the pathological relevance of molecules known to accumulate and positively correlate with CVD severity is vital, and this avenue of research has important therapeutic potential for Veterans. Approximately 25% of the more than 8 million current Veterans Affairs (VA) medical system users suffer from ischemic heart disease due to atherosclerosis. This is alarming, especially considering that atherosclerosis is a disease for which no cure exists, despite over 50 years of active research on the subject. [In addition, increased risk for atherosclerosis is associated with PTSD and injuries resulting in amputation. Given the growing number of Veterans suffering from both of these clinical complications the need to understand basic mechanisms of atherosclerosis is crucial.] Therefore, it is imperative that we continue to identify therapeutic targets in order to provide a basis for cutting edge treatments for CVD.