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

心血管疾病（CVD）每年导致大约100万美国人死亡。研究 显示50岁以上的退伍军人患CVD的风险增加。动脉粥样硬化，最常见的形式 心血管疾病是一种无菌性炎症疾病，其特征是动脉中斑块的积累。起初， 低密度脂蛋白（LDL）在血管系统中积累，随后在血管系统中被氧化 氧化低密度脂蛋白（oxLDL）并对局部组织造成损伤。这导致先天性和适应性免疫的激活， oxLDL特异性IgG的产生。oxLDL特异性抗体和所得免疫复合物的滴度 已知oxLDL-IC与疾病严重程度相关，但尚不清楚oxLDL-IC是否在疾病中发挥作用。 发病机制IC可通过与Fc γ受体相互作用调节动脉粥样硬化中的炎症 在DC的表面上表达的FcgR。激活性（FcgRI/III）和抑制性（FcgRIIb）FcgRs介导 相反的功能在DC，转移之间的平衡促炎DC活化和耐受性 应答我们已发表的研究表明，oxLDL-IC启动炎性小体的作用比 游离oxLDL。这主要是通过诱导FcgR和TLR串扰激活Card 9，Malt 1， BCL 10复合物扩增NF-κ B B核转位。此外，抑制性FcgRIIb的缺乏也会导致细胞凋亡。 CD 11 c+细胞增加雌性而非雄性Ldlr-/-小鼠的动脉粥样硬化， oxLDL-IC增加斑块大小。初步数据表明，oxLDL-IC可能允许DC促进TH 17 反应并抑制TH 1细胞产生IFN-g。产生IL-17的T细胞的增加依赖于 IL-1b而IFN-g降低可能是由于对oxLDL-IC应答的IL-23增加。这些数据表明 oxLDL-IC可以作为内源性危险信号，或DAMP，并有能力塑造 动脉粥样硬化炎症反应。使用体外和体内模型，本发明的长期目标是： 研究旨在确定oxLDL-IC通过FcgRs信号传导调节免疫的机制， 动脉粥样硬化我们假设：1）oxLDL-IC许可DC增强促炎性CD 4 + T细胞 通过表观遗传学和代谢机制的反应; 2）oxLDL-IC增强炎症 在动脉粥样硬化通过训练免疫的DC，和3）这些反应中的许多是依赖于性别- 荷尔蒙有机会检验这一假设将使我们能够继续制定“大图景” 关于oxLDL-IC在CVD中作用的结论。除了假设驱动的研究，我们将进行 代谢组学和表观遗传学研究，使我们能够做出新颖和创新的假设。理解 已知与CVD严重程度正相关的分子的病理学相关性是 至关重要，这种研究途径对退伍军人具有重要的治疗潜力。大约25%的 目前，超过800万退伍军人事务部（VA）医疗系统用户患有缺血性心脏病， 动脉粥样硬化这是令人担忧的，特别是考虑到动脉粥样硬化是一种无法治愈的疾病 尽管对这个问题进行了50多年的积极研究，但仍然存在。此外，研究性激素在 考虑到近10%的退伍军人是女性，我们观察到的反应至关重要。这些研究将填补 关于动脉粥样硬化的知识存在重大差距，并将最终导致改善我们的治疗。 退伍军人和他们的家人。

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.