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GR-AMPK - Crosstalk of Glucocorticoid Receptor and AMP-induced Kinase in macrophages during inflammation and tissue repair

GR-AMPK - 炎症和组织修复过程中巨噬细胞中糖皮质激素受体和 AMP 诱导激酶的串扰

基本信息

批准号：
283865434
负责人：
Professor Dr. Jan Tuckermann
金额：
--
依托单位：
Institut für Molekulare Endokrinologie der Tiere
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 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/283865434?language=en
关键词：
GR AMPK Crosstalk Glucocorticoid Receptor

项目摘要

Inflammation after infectious or sterile traumatic insult and its subsequent resolution is a balanced process to combat pathogens and to induce tissue repair while avoiding aberrant inflammation induced organ damage. Macrophages are central players by participating in both inflammatory and repair processes and by skewing from a pro- to an anti-inflammatory repair phenotype. Glucocorticoids (GCs), which belong to the most active anti-inflammatory substances, were shown by the German team to be critically involved in macrophages to suppress inflammation in mouse models of contact allergy, experimental encephalomyelitis and septic shock. Furthermore they show that in a model of acute lung injury the combined action of the GC receptor (GR) and the MAP kinase p38 results in the induction of an anti-inflammatory marker gene necessary to resolve lung inflammation. By this they identified a novel mechanism how GCs suppress inflammation. Strikingly similar are anti-inflammatory activities of the fuel-sensing enzyme 5'AMP-activated protein kinase (AMPK). Absence of AMPK increases pro-inflammatory cytokine expression, whereas AMPK activation induces the expression of anti-inflammatory markers. The French group demonstrated that AMPK activation is required for a proper repair of damaged muscle by inducing an anti-inflammatory phenotype in macrophages. Common preliminary work now provide evidence that i) GCs influence muscle repair dependent on AMPK in vitro, that ii) anti-inflammatory effects of GCs is lost in AMPK-deficient macrophages and that iii) AMPK-phosphorylation is enhanced by GCs. We therefore hypothesize that GR and AMPK act in concert and mutually interact to achieve their anti-inflammatory properties in macrophages, essential to resolve inflammation and to induce tissue repair. We will characterize the crosstalk of AMPK and GR activation in macrophages during immune challenges and tissue repair by using conditional GR and AMPK mutant mice exposed to GR and AMPK activators. We will determine how GR and AMPK in concert regulate inflammatory mediators and control the dynamics to adopt anti-inflammatory macrophage phenotype. We will address in an acute lung inflammation model (non sterile inflammation) and in a muscle repair model (sterile inflammation) how AMPK contributes to the therapeutic actions of GCs and vice versa. We will further exploit a potential cooperative activity of GCs and AMPK activators as a possibility to reduce GC dosage and thus to avoid side effects of GC therapy. We expect from this integrative project insights into the interference of AMPK and GR signaling as a novel paradigm of immune suppression, which could give the base for new rationales to improve steroid therapies and tissue repair.

感染性或无菌创伤性损伤后的炎症及其随后的消退是对抗病原体和诱导组织修复同时避免异常炎症诱导的器官损伤的平衡过程。巨噬细胞通过参与炎症和修复过程以及通过从促炎修复表型向抗炎修复表型倾斜而成为中心参与者。糖皮质激素（GC）是最活跃的抗炎物质，德国研究小组发现，在接触性过敏、实验性脑脊髓炎和感染性休克小鼠模型中，GC与巨噬细胞抑制炎症密切相关。此外，他们表明，在急性肺损伤模型中，GC受体（GR）和MAP激酶p38的联合作用导致诱导解决肺部炎症所必需的抗炎标志物基因。通过这一点，他们确定了GC抑制炎症的新机制。燃料敏感酶5'AMP激活蛋白激酶（AMPK）的抗炎活性惊人地相似。AMPK的缺乏增加促炎细胞因子的表达，而AMPK激活诱导抗炎标志物的表达。法国研究小组证明，通过诱导巨噬细胞中的抗炎表型，AMPK激活是正确修复受损肌肉所需的。现在，常见的初步工作提供了以下证据：i）GC影响体外依赖于AMPK的肌肉修复，ii）GC的抗炎作用在AMPK缺陷的巨噬细胞中丧失，iii）GC增强AMPK磷酸化。因此，我们假设GR和AMPK协同作用并相互作用以实现其在巨噬细胞中的抗炎特性，这对于解决炎症和诱导组织修复至关重要。我们将通过使用暴露于GR和AMPK激活剂的条件性GR和AMPK突变小鼠来表征免疫挑战和组织修复期间巨噬细胞中AMPK和GR激活的串扰。我们将确定GR和AMPK如何协同调节炎症介质并控制动力学以采用抗炎巨噬细胞表型。我们将在急性肺部炎症模型（非无菌炎症）和肌肉修复模型（无菌炎症）中讨论AMPK如何有助于GC的治疗作用，反之亦然。我们将进一步开发GC和AMPK激活剂的潜在合作活性，以减少GC剂量，从而避免GC治疗的副作用。我们期望从这个综合项目中了解AMPK和GR信号传导的干扰作为免疫抑制的新范例，这可以为改善类固醇治疗和组织修复提供新的理论基础。