A Role of Isolevuglandin Adducts in Essential Hypertension and Systemic Lupus Erythematosus

异左旋黄素加合物在原发性高血压和系统性红斑狼疮中的作用

• 批准号: 10222781
• 负责人: David Patrick
• 金额: $ 15.84万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222781
• 关键词: Angiotensin II; Animals; Antigen Presentation; Antigen-Presenting Cells; Aortitis; Attenuated; Autoantibodies; Autoantigens; Autoimmune Diseases; Biological Assay; Bone Marrow; Bortezomib; Cardiovascular Diseases; Cell surface; Cells; Characteristics; Clinical; Complex; Data; Dendritic Cells; Development; Disease; Essential Hypertension; Exhibits; Experimental Models; Fatty Acids; Fellowship; Flow Cytometry; Fluorescence Resonance Energy Transfer; Human; Hypertension; ITGAX gene; Immune Tolerance; Immunosuppression; Incidence; Inflammation; Kidney Diseases; Knowledge; Lupus; Lysine; MHC Class I Genes; Mentors; Modeling; Mus; Organ; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Plasma Cells; Population; Positioning Attribute; Process; Proteasome Inhibitor; Proteins; Publishing; Reactive Oxygen Species; Research; Role; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissues; Transgenic Animals; Woman; adduct; autoimmune pathogenesis; autoreactive T cell; base; blood pressure reduction; career; chymotrypsin; conditional knockout; curative treatments; design; disease heterogeneity; experience; immune activation; inhibitor/antagonist; insight; monocyte; mouse model; multicatalytic endopeptidase complex; neoantigens; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; oxidation; patient subsets; peroxidation; prevent; recruit; response; systemic autoimmunity

PROJECT SUMMARY Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions. An estimated one- third of the world’s population suffers from hypertension despite a large number of treatment options. SLE is a heterogeneous disease the treatment of which is limited to the use of non-specific global immunosuppression. There is a lack of understanding of the mechanisms underlying these conditions. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation, hypertension, and systemic autoimmunity. Based upon previously published studies and preliminary data, it is clear that both essential hypertension and SLE are initiated by this process of isoLG-adduct formation, processing, and immune cell activation. I have discovered an important role of the immunoproteasome in the presentation of isoLG-adducted autoantigens, the development of hypertension, and aortic inflammation in a mouse model of essential hypertension. Moreover, in a mouse model of SLE, I have also discovered that treatment of mice with an isoLG scavenger, 2-hydroxybenzylamine, attenuates hypertension and systemic autoimmunity. Finally, I found that a subset of patients with SLE exhibit isoLG accumulation within antigen presenting cells, suggesting a unique clinical profile and potential therapeutic opportunities for these patients. I hypothesize that within antigen presenting cells, isoLG adducts are processed and displayed by an immunoproteasome dependent mechanism. Additionally, patients with SLE that exhibit isoLG-adduct accumulation exhibit unique disease characteristics. My specific aims are: (1) To determine a role of isoLG- adducts in SLE-associated hypertension and disease heterogeneity. (2) To determine the role of immunoproteasome function in isoLG antigen presentation and hypertension. To accomplish these aims we will recruit SLE patients and obtain peripheral blood mononuclear cells. Cells will be studied by flow cytometry for the presence of isoLG-adduct accumulation within specific populations of antigen presenting cells. IsoLG-adduct levels will be compared with clinical parameters to determine the characteristics that correlate with adduct accumulation. To study the function of the immunoproteasome, I will utilize mice globally deficient for the three subunits of the immunoproteasome (TKO mice). I have also generated a conditional knockout of the chymotrypsin subunit of the immunoproteasome (LMP7fl/fl) which will be crossed to CD11c-Cre transgenic animals to generate an antigen presenting cell specific LMP7 deficient animal. These animals will be studied for the development of hypertension and inflammation in the setting of two well established acquired models of essential hypertension in mice. Together, these studies hold the promise of elucidating novel mechanistic insights into essential hypertension and SLE. Moreover, they will provide novel therapeutic opportunities for the treatment of these conditions.

项目概要 原发性高血压和系统性红斑狼疮 (SLE) 是毁灭性的疾病。估计一—— 尽管有多种治疗选择，但世界上仍有三分之一的人口患有高血压。系统性红斑狼疮是一种 异质性疾病，其治疗仅限于使用非特异性整体免疫抑制。 人们对这些病症背后的机制缺乏了解。异黄兰素 (IsoLG) 是 由于活性氧而形成的脂肪酸的氧化产物。这些分子加合物 与蛋白质的赖氨酸残基共价。然后加合的蛋白质作为自身抗原呈递给 T 细胞 导致免疫细胞激活、高血压和全身性自身免疫。基于之前发布的 研究和初步数据显示，很明显，原发性高血压和系统性红斑狼疮都是由这一过程引发的。 isoLG 加合物的形成、加工和免疫细胞激活。我发现了一个重要的角色 免疫蛋白酶体在 isoLG 加合自身抗原的呈递、高血压的发展和 原发性高血压小鼠模型中的主动脉炎症。此外，在 SLE 小鼠模型中，我还 发现用 isoLG 清除剂 2-羟基苯甲胺治疗小鼠可以减轻高血压和 系统性自身免疫。最后，我发现一部分 SLE 患者在体内表现出 isoLG 积累 抗原呈递细胞，表明这些细胞具有独特的临床特征和潜在的治疗机会 患者。我假设在抗原呈递细胞内，isoLG 加合物由 免疫蛋白酶体依赖性机制。此外，表现出 isoLG 加合物的 SLE 患者 积累表现出独特的疾病特征。我的具体目标是：（1）确定 isoLG- 的作用 SLE 相关高血压和疾病异质性中的加合物。 (2) 确定角色 免疫蛋白酶体在 isoLG 抗原呈递和高血压中的功能。为了实现这些目标，我们将 招募SLE患者并获取外周血单核细胞。将通过流式细胞术研究细胞 特定抗原呈递细胞群内isoLG加合物积累的存在。 IsoLG加合物 水平将与临床参数进行比较，以确定与加合物相关的特征 积累。为了研究免疫蛋白酶体的功能，我将利用全面缺乏这三种免疫蛋白酶体的小鼠 免疫蛋白酶体的亚基（TKO 小鼠）。我还生成了一个有条件的淘汰赛 免疫蛋白酶体 (LMP7fl/fl) 的糜蛋白酶亚基，将与 CD11c-Cre 转基因杂交 动物产生抗原呈递细胞特异性LMP7缺陷动物。这些动物将被研究 在两个完善的获得性模型中高血压和炎症的发展 小鼠原发性高血压。总之，这些研究有望阐明新的机制 对原发性高血压和 SLE 的见解。此外，它们将为患者提供新的治疗机会 治疗这些情况。

项目成果

The role of inflammation in hypertension: novel concepts.

• DOI: 10.1016/j.cophys.2020.09.016
• 发表时间: 2021-03
• 期刊: Current opinion in physiology
• 影响因子: 2.5
• 作者: Patrick DM;Van Beusecum JP;Kirabo A
• 通讯作者: Kirabo A

Increased Development of Th1, Th17, and Th1.17 Cells Under T1 Polarizing Conditions in Juvenile Idiopathic Arthritis.

• DOI: 10.3389/fimmu.2022.848168
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Patrick, Anna E.;Shoaff, Kayla;Esmond, Tashawna;Patrick, David M.;Flaherty, David K.;Graham, T. Brent;Crooke, Philip S.;Thompson, Susan;Aune, Thomas M.
• 通讯作者: Aune, Thomas M.

Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus.

• DOI: 10.1172/jci.insight.136678
• 发表时间: 2022-07-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Patrick, David M.;Visitacion, Nestor de la;Krishnan, Jaya;Chen, Wei;Ormseth, Michelle J.;Stein, C. Michael;Davies, Sean S.;Amarnath, Venkataraman;Crofford, Leslie J.;Williams, Jonathan M.;Zhao, Shilin;Smart, Charles D.;Dikalov, Sergey;Dikalova, Anna;Xiao, Liang;Van Beusecum, Justin P.;Ao, Mingfang;Fogo, Agnes B.;Kirabo, Annet;Harrison, David G.
• 通讯作者: Harrison, David G.

Growth Arrest Specific-6 and Axl Coordinate Inflammation and Hypertension.

• DOI: 10.1161/circresaha.121.319643
• 发表时间: 2021-11-12
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Van Beusecum, Justin P.;Barbaro, Natalia R.;Smart, Charles D.;Patrick, David M.;Loperena, Roxana;Zhao, Shilin;de la Visitacion, Nestor;Ao, Mingfang;Xiao, Liang;Shibao, Cyndya A.;Harrison, David G.
• 通讯作者: Harrison, David G.

IsoLGs (Isolevuglandins) Drive Neutrophil Migration in Hypertension and Are Essential for the Formation of Neutrophil Extracellular Traps.

• DOI: 10.1161/hypertensionaha.122.19305
• 发表时间: 2022-08
• 期刊: HYPERTENSION
• 影响因子: 8.3
• 作者: Krishnan, Jaya;de la Visitacion, Nestor;Hennen, Elizabeth M.;Amarnath, Venkataraman;Harrison, David G.;Patrick, David M.
• 通讯作者: Patrick, David M.