Fc Receptors in Atherosclerosis: Linking Innate and Adaptive Immunity.

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Cardiovascular disease (CVD) accounts for the deaths of approximately 1 million Americans annually. Studies show that Veterans over the age of 50 are at increased risk for CVD. Atherosclerosis, the most common form of CVD, is a disease of sterile inflammation characterized by accumulation of plaque in the arteries. Initially, low density lipoproteins (LDL) accumulates in the vasculature where they subsequently become oxidized (oxLDL) and cause damage to local tissue. This results in activation of innate and adaptive immunity and production of oxLDL-specific IgG. Titers of oxLDL-specific antibodies 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 (FcgRs) expressed on the surface of DCs. Activating (FcgRI/III) and inhibitory (FcgRIIb) FcgRs mediate opposing functions in DCs, shifting the balance between pro-inflammatory DC activation and tolerogenic responses. Our published studies demonstrate that oxLDL-ICs prime the inflammasome more robustly than free oxLDL. This was primarily through induction of FcgR and TLR cross talk activating the Card9, Malt1, BCL10 complex to amplify NF-B nuclear translocation. In addition, absence of the inhibitory FcgRIIb on CD11c+ cells increased atherosclerosis in female but not male Ldlr-/- mice and injection of Ldlr-/- mice with oxLDL-ICs increases plaque size. Preliminary data suggest that oxLDL-ICs may license DCs to promote TH17 responses and inhibit IFN-g production by TH1 cells. The increase in IL-17 producing T cells is dependent on IL-1b while decreased IFN-g is likely due to increased IL-23 in response to oxLDL-ICs. These data suggest that oxLDL-ICs can act as endogenous danger signals, or DAMPs, and have the ability to shape the inflammatory response in atherosclerosis. Using both in vitro and in vivo models, the long term goal of this study is to determine the mechanisms by which oxLDL-ICs signaling through FcgRs modulate immunity in atherosclerosis. We hypothesize that 1) oxLDL-ICs licence DCs to enhance pro-inflammatory CD4+ T cell responses through mechanisms involving epigenetics and metabolism; 2) oxLDL-ICs potentiate inflammation in atherosclerosis via trained immunity in DCs, and 3) many of these responses are dependent on sex- hormones. Being afforded the opportunity to test this hypothesis will allow us to continue to make “big picture” conclusions regarding the role of oxLDL-ICs in CVD. In addition to hypothesis-driven studies, we will conduct metabolomic and epigenetic studies that will allow us to make novel and innovative hypotheses. 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, studying the role that sex hormones play in our observed responses is critical given that close to 10% of Veterans are women. These studies will fill significant gaps in knowledge concerning atherosclerosis and will ultimately lead to improved treatment of our Veterans and their families.