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心血管疾病的风险增加。动脉粥样硬化，最常见的形式 心血管疾病是一种以动脉内斑块堆积为特征的无菌炎症疾病。最初， 低密度脂蛋白(LDL)在血管中积聚，在那里它们随后被氧化 (OxLDL)，并对局部组织造成损害。这会激活先天免疫和获得性免疫， 产生ox低密度脂蛋白特异性免疫球蛋白。OxLDL特异性抗体的滴度和由此产生的免疫复合体 (oxLDL-ICs)已知与疾病严重程度相关，目前尚不清楚oxLDL-ICs在疾病中是否起作用 发病机制。ICS通过与Fcγ受体相互作用调节动脉粥样硬化的炎症反应 (FcgRs)表达于DC表面。激活(FcgRI/III)和抑制(FcgRIIb)FcgRs介导 DC的相反功能，改变了促炎DC激活和耐受性之间的平衡 回应。我们已发表的研究表明，oxLDL-ICs对炎症小体的激活作用比 游离oxLDL。这主要是通过诱导FcgR和TLR串扰激活CARD9，Malt1， Bcl10复合体，扩增核转录因子-B核转位。此外，缺乏抑制FcgRIIb对 CD11c+细胞增加雌性Ldlr-/-小鼠动脉粥样硬化，但不增加雄性Ldlr-/-小鼠动脉粥样硬化 OxLDL-ICs可增加斑块大小。初步数据显示，oxLDL-ICs可能会授权DC推广TH17 并抑制TH1细胞产生干扰素-g。产生IL-17的T细胞的增加依赖于 而IL-1b的降低可能是由于oxLDL-ICs导致IL-23升高所致。这些数据表明 OxLDL-ICs可以作为内源性危险信号或阻尼器，并有能力塑造 动脉粥样硬化中的炎症反应。使用体外和体内模型，这项研究的长期目标 研究目的是确定oxLDL-ICs通过FcgRs信号调节免疫的机制。 动脉硬化。我们假设1)oxLDL-ICs许可DC增强促炎的CD4+T细胞 通过表观遗传和代谢机制作出反应；2)oxLDL-ICs增强炎症 在动脉粥样硬化中，通过DC中训练的免疫，以及3)这些反应中的许多依赖于性别- 荷尔蒙。被给予检验这一假设的机会将使我们能够继续作出“大图景” 结论：oxLDL-ICs在心血管疾病中的作用。除了假设驱动的研究外，我们还将进行 代谢学和表观遗传学研究将使我们能够提出新的和创新的假设。理解 已知的与CVD严重程度呈正相关并累积的分子的病理相关性是 至关重要，这一研究途径对退伍军人具有重要的治疗潜力。约25%的 超过800万当前退伍军人事务部(VA)医疗系统用户患有缺血性心脏病 致动脉粥样硬化。这令人担忧，尤其是考虑到动脉粥样硬化是一种无法治愈的疾病。 尽管对这个主题进行了50多年的积极研究，但它仍然存在。此外，研究性激素在体内的作用 鉴于近10%的退伍军人是女性，在我们观察到的反应中发挥作用是至关重要的。这些研究将填补 在有关动脉粥样硬化的知识方面存在重大差距，并最终将导致改善我们的 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.