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The mineralocorticoidreceptor in myeloid cells - a new player in CNS autoimmunity

骨髓细胞中的盐皮质激素受体——中枢神经系统自身免疫的新参与者

基本信息

批准号：
273444380
负责人：
Privatdozent Dr. Fred Lühder
金额：
--
依托单位：
Institut für Zelluläre und Molekulare Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/273444380?language=en
关键词：
mineralocorticoidreceptor myeloid cells new player

项目摘要

Our previous work focused on the role of the glucocorticoid receptor (GR) in T cells for the pathogenesis of EAE and multiple sclerosis (MS). However, there is another receptor capable of binding glucocorticoids (GCs) besides the GR, namely the mineralocorticoid receptor (MR), which is expressed in myeloid cells and could therefore mediate relevant effects of GCs in the modulation of neuroinflammatory diseases. Therefore we performed several pilot experiments which suggested that disruption of the MR in myeloid cells has a significant impact on EAE as well. Hence, the purpose of the follow-up project is to explore the role of the MR in the control of neuroinflammation by GCs in more detail and to identify the mechanisms involved. In the first part of the project we want to study EAE in myeloid cell-specific MR knock-out mice (MRlysM). This includes a detailed phenotypic and functional characterization of different types of myeloid cells during the course of EAE, both in peripheral lymphoid organs and the CNS. These studies will be complemented by immunohistochemical analyses of the spinal cord. Since the MR is expressed in distinct subtypes of myeloid cells we will investigate whether their composition is altered and to which extent the microglia contributes to the observed phenotype. In addition, we want to study pathogenic T cells which might be indirectly affected by the absence of the MR in myeloid cells. In the second part we plan to analyze migration of myeloid cells. Because CNS infiltration of macrophages is diminished in MRlysM mice we will perform in vitro transmigration assays of myeloid cells obtained from naïve and EAE mice. Subsequently, we will use 2-photon microscopy to test in vivo whether and how MR-deficiency may affect monocyte migration in response to different stimuli. In the third part we will built upon our finding that application of the MR antagonist Aldactone® ameliorates EAE. Initially, we will compare two different application protocols and then try to understand the mechanism underlying pharmacological MR blockade. Collectively, we expect that our studies will clarify the role of the MR in myeloid cells for the pathogenesis and therapy of neuroinflammatory diseases and allow a first assessment of whether MR antagonists might be suitable for the treatment of CNS inflammation in patients. Since such inhibitors are already in clinical use, our results might pave the way for translational studies in the future.

我们以前的工作集中在糖皮质激素受体（GR）在T细胞的发病机制EAE和多发性硬化症（MS）的作用。然而，除了GR之外，还有另一种能够结合糖皮质激素（GC）的受体，即盐皮质激素受体（MR），其在髓样细胞中表达，因此可以介导GC在神经炎性疾病的调节中的相关作用。因此，我们进行了几个试点实验，这表明破坏髓系细胞中的MR对EAE也有显着影响。因此，后续项目的目的是更详细地探索MR在GC控制神经炎症中的作用，并确定所涉及的机制。在该项目的第一部分，我们想研究EAE在骨髓细胞特异性MR基因敲除小鼠（MRlysM）。这包括EAE过程中外周淋巴器官和CNS中不同类型髓样细胞的详细表型和功能特征。这些研究将通过脊髓的免疫组织化学分析进行补充。由于MR是在不同亚型的骨髓细胞中表达，我们将研究它们的组成是否改变，以及在何种程度上小胶质细胞有助于观察到的表型。此外，我们想研究可能间接受骨髓细胞中MR缺失影响的致病性T细胞。在第二部分中，我们计划分析骨髓细胞的迁移。由于巨噬细胞的CNS浸润在MRlysM小鼠中减少，我们将对从幼稚和EAE小鼠获得的骨髓细胞进行体外迁移测定。随后，我们将使用双光子显微镜在体内测试MR缺陷是否以及如何影响单核细胞迁移反应不同的刺激。在第三部分中，我们将建立在我们的发现基础上，即MR拮抗剂Aldactone®的应用改善了EAE。首先，我们将比较两种不同的应用方案，然后尝试了解药理学MR阻滞的机制。总的来说，我们希望我们的研究将阐明髓系细胞中MR在神经炎性疾病发病机制和治疗中的作用，并首次评估MR拮抗剂是否适用于治疗患者的CNS炎症。由于这种抑制剂已经在临床上使用，我们的结果可能为未来的转化研究铺平道路。