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

Fc§§ 动脉粥样硬化受体：连接先天免疫和适应性免疫。

• 批准号: 10450688
• 负责人: AMY S MAJOR
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450688
• 关键词: Affect; Age; American; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Aorta; Arteries; Atherogenic Diet; Atherosclerosis; B-Lymphocytes; BCL10 gene; Biological; Bone Marrow; CD11c Antigens; CD36 gene; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Cessation of life; Chimera organism; Cholesterol; Chronic; Complex; Data; Dendritic Cells; Dendritic cell activation; Disease; Disease Progression; Epigenetic Process; Equilibrium; Estrogen Replacements; Exposure to; Family; Fc Receptor; Female; Gene Expression Regulation; General Population; Glycolysis; Goals; Gonadal Steroid Hormones; Health; Hepatic; Human; Hyperlipidemia; ITGAX gene; IgG Receptors; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologic Factors; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injections; Interferon Type II; Interleukin-17; Knowledge; Lead; Licensing; Ligation; Link; Lipoproteins; Liver; Low-Density Lipoproteins; Mediating; Medical; Memory; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Myocardial Ischemia; Natural Immunity; Nuclear Translocation; Oxides; Pathogenesis; Pathologic; Patients; Pattern; Play; Production; Publishing; Receptor Signaling; Regulatory T-Lymphocyte; Research; Role; Severity of illness; Sex Differences; Shapes; Signal Pathway; Signal Transduction; Sterility; Stimulus; Surface; System; T cell response; T-Lymphocyte; TLR4 gene; Testing; Th1 Cells; Therapeutic; Tissues; Training; Triglycerides; United States Department of Veterans Affairs; Up-Regulation; Veterans; Woman; Work; XCL1 gene; adaptive immunity; antigen-specific T cells; atherogenesis; cardiovascular disorder risk; cytokine; draining lymph node; epigenetic regulation; improved; in vivo; in vivo Model; innovation; interleukin-23; macrophage; male; metabolomics; military veteran; mortality; neutrophil; new therapeutic target; novel; oxidized LDL receptors; oxidized low density lipoprotein; response; sex

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.

心血管疾病 (CVD) 每年导致约 100 万美国人死亡。 研究表明，50 岁以上的退伍军人患动脉粥样硬化（最常见的疾病）的风险增加。 CVD 是一种无菌性炎症疾病，其特征是动脉中斑块积聚。 低密度脂蛋白 (LDL) 在脉管系统中积聚，随后被氧化 (oxLDL) 并对局部组织造成损伤，从而激活先天性和适应性免疫并 oxLDL 特异性 IgG 的产生以及由此产生的免疫复合物。 (oxLDL-IC) 已知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 IC 可以通过与 Fc γ 受体相互作用来调节动脉粥样硬化中的炎症。 (FcgR) 在 DC 表面表达，激活 (FcgRI/III) 和抑制 (FcgRIIb) FcgR 介导。 DC 中相反的功能，改变了促炎性 DC 激活和耐受性之间的平衡 我们发表的研究表明，oxLDL-IC 比 oxLDL-IC 更能引发炎症小体。 这主要是通过诱导 FcgR 和 TLR 串扰激活 Card9、Malt1、 BCL10 复合物可放大 NF-κB 核转位 此外，缺乏抑制性 FcgRIIb。 CD11c+细胞增加雌性而非雄性Ldlr-/-小鼠的动脉粥样硬化，并且注射Ldlr-/-小鼠 oxLDL-ICs 增加斑块大小，初步数据表明 oxLDL-ICs 可能允许 DC 促进 TH17。 反应并抑制 TH1 细胞产生 IFN-g。产生 IL-17 的 T 细胞的增加取决于 IL-1b 而 IFN-g 的减少可能是由于 oxLDL-IC 导致 IL-23 增加所致。这些数据表明。 oxLDL-IC 可以充当内源性危险信号 (DAMP)，并且能够塑造 使用体外和体内模型研究动脉粥样硬化的炎症反应，这是该研究的长期目标。 研究的目的是确定 oxLDL-ICs 通过 FcgRs 信号传导调节免疫的机制 我们勇敢地面对 1) oxLDL-IC 许可 DC 增强促炎性 CD4+ T 细胞 通过涉及表观遗传学和代谢的机制做出反应；2) oxLDL-IC 增强炎症 通过树突状细胞中训练有素的免疫力来预防动脉粥样硬化，并且3）许多这些反应都依赖于性别- 有机会检验这一假设将使我们能够继续描绘“大局”。 关于 oxLDL-IC 在 CVD 中的作用的结论 除了假设驱动的研究外，我们还将进行。 代谢组学和表观遗传学研究将使我们能够做出新颖和创新的假设。 已知积累并与 CVD 严重程度呈正相关的分子的病理相关性是 至关重要，这一研究途径对大约 25% 的退伍军人具有重要的治疗潜力。 目前退伍军人事务部 (VA) 医疗系统中有超过 800 万用户患有缺血性心脏病 这令人震惊，特别是考虑到动脉粥样硬化是一种无法治愈的疾病。 尽管对这一主题的研究已有 50 多年的历史，但性激素的作用仍然存在。 鉴于近 10% 的退伍军人是女性，我们观察到的反应至关重要。这些研究将填补这一空白。 关于动脉粥样硬化的知识存在巨大差距，最终将导致我们的治疗方法得到改善 退伍军人及其家人。