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）每年约有100万美国人死亡。研究 表明50岁以上的退伍军人的CVD风险增加。动脉粥样硬化，最常见的形式 CVD的疾病是一种无菌炎症疾病，其特征是动脉中斑块的积累。最初， 低密度脂蛋白（LDL）积聚在脉管系统中，随后它们被氧化 （OXLDL）并损害局部组织。这导致激活先天和适应性免疫组织化学和 OXLDL特异性IgG的产生。 OXLDL特异性抗体和产生的免疫复合物的滴度 （OXLDL-ICS）已知与疾病的严重程度相关，尚不清楚Oxldl-ICS是否在疾病中起作用 发病。 IC可以通过与FC伽马受体相互作用来调节动脉粥样硬化的炎症 （FCGRS）在DC表面表达。激活（FCGRI/III）和抑制（FCGRIIB）FCGRS介导 DC中相对的功能，在促炎DC激活和耐受性之间移动平衡 回答。我们发表的研究表明，oxldl-ics比炎性体比 自由oxldl。这主要是通过诱导FCGR和TLR交叉谈话激活Card9，Malt1， BCl10复合物可以扩增NF-B核易位。另外，没有抑制性fcgriib CD11C+细胞增加了女性但雄性LDLR - / - 小鼠的动脉粥样硬化，并注射了LDLR - / - 小鼠 OXLDL-ICS增加了斑块大小。初步数据表明OXLDL-ICS可以许可DC促进TH17 反应并抑制Th1细胞产生的IFN-G产生。 IL-17产生T细胞的增加取决于 IL-1b虽然IFN-G降低可能是由于响应OXLDL-IS的IL-23增加。这些数据暗示 OXLDL-ICS可以充当内源性危险信号或潮湿，并具有成型的能力 动脉粥样硬化中的炎症反应。使用体外和体内模型，这是此的长期目标 研究是为了确定OXLDL-ICS通过FCGRS通过FCGR调节免疫原子的机制 动脉粥样硬化。我们假设1）OXLDL-ICS许可DCS增强促炎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-ICS潜在注入 在动脉粥样硬化中通过训练有素的DC中的免疫力，3）其中许多反应取决于性别 骑马。获得检验这一假设的机会将使我们能够继续制作“大局” 关于oxldl-ics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。理解 丙烯酸已知并与CVD严重程度正相关的分子的病理相关性是 至关重要的，这一研究途径对退伍军人具有重要的治疗潜力。大约25％ 当前有超过800万当前退伍军人事务（VA）医疗系统使用者患有缺血性心脏病 动脉粥样硬化。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 存在，目的地超过50年，对该主题进行了积极研究。此外，研究性恐怖的角色 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至关重要。这些研究将填补 关于动脉粥样硬化的知识差距很大，最终将改善对我们的治疗 退伍军人及其家人。