Role of Estrogen Receptors in Lupus-Modulators of the Inflammatory Response

雌激素受体在狼疮炎症反应调节剂中的作用

• 批准号: 8391533
• 负责人: Gary S Gilkeson
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391533
• 关键词: Address; Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Antibody Complex; Area; Autoantibodies; Autoimmune Diseases; B-Cell Activation; B-Lymphocytes; Backcrossings; Binding; Biological Preservation; Bone Marrow Transplantation; CCL2 gene; Calcineurin; Caring; Cell Count; Cell Line; Cell Nucleus; Cells; Clinic; Congenic Mice; Development; Disease; Epigenetic Process; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Family; Female; Funding; Gender; Genes; Genotype; Glomerulonephritis; Gonadal Steroid Hormones; Hormone Receptor; IL6 gene; Immune; Immune response; Immunity; Immunoglobulin G; In Vitro; Inflammation; Inflammatory Response; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Ligand Binding; Ligands; Lupus; Lupus Nephritis; Mediating; Mediator of activation protein; Medical; Minority; Molecular; Mus; NZW Mouse; Nuclear Hormone Receptors; Nuclear Translocation; Organ; Pathogenesis; Pathologic; Pathway interactions; Patients; Phosphorylation; Physiological; Population; Prevalence; Production; Promoter Regions; Proteinuria; Publications; Receptor Signaling; Renal function; Research; Response Elements; Role; SLEB1 gene; Serum; Sex Characteristics; Sex Chromosomes; Signal Transduction; Small Interfering RNA; Somatic Mutation; Systemic Lupus Erythematosus; T-Lymphocyte; TLR3 gene; Testing; Tissues; Toll-Like Receptor 2; Toll-like receptors; Tumor Necrosis Factor-alpha; Veterans; Woman; X Inactivation; abstracting; anti-dsDNA antibodies; base; cell type; congenic; expectation; human TNF protein; in vivo; insight; interest; lupus prone mice; macrophage; male; men; mesangial cell; mortality; mutant; new therapeutic target; novel; novel strategies; promoter; protective effect; receptor; receptor expression; response; sle1/sle3 gene

Abstract Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by autoantibody production and immune complex mediated organ damage. One of the more profound features of SLE is females having a 9:1 prevalence of disease over men. The cause of this gender difference in SLE is multifactorial, including the sex hormones themselves and their receptors. Estrogen acts primarily via its receptors, estrogen receptor alpha and beta (ER¿/ER¿). Estrogen can also act, however, through non-receptor mediated mechanisms and, in kind, the ERs mediate physiologic functions independent of estrogen. In the previous funding period, we derived ER¿ and ER¿ knockout lupus prone MRL/lpr and NZM2410 mice. In both strains, the female ER¿ KOs developed significantly less proteinuria and pathologic renal disease and had significantly prolonged survival, despite increased serum levels of autoantibodies. These findings led us to postulate that the primary impact of ER¿ deficiency in lupus nephritis was on the response of the kidney to inflammation. We derived ER¿ KO and ER¿ KO mesangial cells from B6 mice and found that ER¿ KO mesangial cells had a marked blunted response to TLR 2, 3 and 7 ligands. ER¿ expression had no effect on mesangial cell responses as tested. Based on these findings, we hypothesize that the lack of ER¿ is renal protective in female lupus mice by blunting the response of mesangial cells to TLR3/7 induced inflammation. We believe this ER¿ protective effect is estrogen independent and mediated via TLR3/7 induced phosphorylation of ER¿. To test this hypothesis, we propose the following Specific Aims: 1. Determine in vivo the effects of ER¿ deficiency on known mechanisms of lupus pathogenesis using sle1, sle3 and sle1/3 congenic mice and bone marrow transplantation of ER¿ KO and ER¿ WT mice. 2. Define the in vitro molecular mechanisms underlying TLR/ER¿ interactions that impact the inflammatory response in mesangial cells assessing the impact of ER¿ on the TLR3/7 activation pathways and TLR3/7 on ER¿ expression. 3. Define in vivo and in vitro the mechanisms by which ER¿ impacts TLR signaling utilizing mutant ER¿ knockin strains that affect specific ER¿ functions allowing delineation of specific ER¿ functions on the immune response. These studies will provide novel insight into the mechanisms by which ER¿ deficiency impacts lupus disease expression and further delineate the interaction between ER¿ and TLR induced inflammation that may partially underlie the female predominance in lupus.

摘要 系统性红斑狼疮（SLE）是一种以自身抗体为特征的典型自身免疫性疾病 产生和免疫复合物介导的器官损伤。SLE的一个更深刻的特征是 女性患病率为男性的9：1。SLE中这种性别差异的原因是 多因素，包括性激素本身及其受体。雌激素主要通过其 受体，雌激素受体α和β（ER <$/ER <$）。然而，雌激素也可以通过非受体 介导的机制，并且在种类上，ER介导不依赖于雌激素的生理功能。在 在前一个资助期，我们获得了ER <$和ER <$敲除狼疮易感MRL/lpr和NZM 2410小鼠。无论是 女性ER科斯患者的蛋白尿和病理性肾脏疾病明显减少， 显著延长生存期，尽管血清自身抗体水平增加。这些发现使我们 假设狼疮性肾炎中ER缺乏的主要影响是肾脏对 炎症我们从B6小鼠中获得ER <$KO和ER <$KO系膜细胞，发现ER <$KO 系膜细胞对TLR 2、3和7配体的反应明显减弱。ER？表达对 肾小球系膜细胞的反应。基于这些发现，我们假设ER的缺乏是 通过减弱系膜细胞对TLR 3/7诱导的反应来保护雌性狼疮小鼠的肾脏 炎症我们认为这种ER保护作用是不依赖雌激素的，并通过TLR 3/7介导。 诱导ER的磷酸化。为了验证这一假设，我们提出了以下具体目标： 1.使用sle 1在体内确定ER缺陷对狼疮发病机制的已知机制的影响， sle 3和sle 1/3同源小鼠以及ER <$KO和ER <$WT小鼠的骨髓移植。 2.定义TLR/ER相互作用的体外分子机制， 肾小球系膜细胞中的反应，评估ER对TLR 3/7活化途径和TLR 3/7 在ER的表达上。 3.在体内和体外定义ER <$影响TLR信号传导的机制，利用突变的ER <$ 敲入菌株影响特定的ER功能，允许在细胞表面描绘特定的ER功能。 免疫反应 这些研究将为ER缺乏影响狼疮疾病的机制提供新的见解 表达，并进一步描述ER和TLR诱导的炎症之间的相互作用， 是狼疮的女性优势的基础

项目成果

Estrogen receptor alpha modulates mesangial cell responses to toll-like receptor ligands.

雌激素受体α调节系膜细胞对Toll样受体配体的反应。

• DOI: 10.1097/maj.0000000000000339
• 发表时间: 2014
• 期刊: The American journal of the medical sciences
• 作者: Svenson,John;Cunningham,Melissa;Dasgupta,Subhajit;Gilkeson,GaryS
• 通讯作者: Gilkeson,GaryS