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The role of IL-1 signaling in the regulation of microglia development and function

IL-1信号在小胶质细胞发育和功能调节中的作用

基本信息

批准号：
317624411
负责人：
Professor Dr. Ari Waisman
金额：
--
依托单位：
Institut für Molekulare Medizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/317624411?language=en
关键词：
role IL signaling regulation microglia

项目摘要

Microglia are brain macrophages that emerge from early erythro-myeloid precursors in the embryonic yolk sac and migrate to the brain mesenchyme prior to the formation of the blood brain barrier. These cells seed the brain, and proliferate until they have formed a grid-like distribution in the central nervous system (CNS) that is maintained throughout lifespan. Recently, we generated a new mouse line that allows for the conditional ablation of microglia cells in adult mice. We found that the microglia compartment was reconstituted within one week after depletion, in a process that relies entirely on CNS-resident cells. By gene expression profiling, we found high expression of the interleukin-1 (IL-1) receptor in repopulating microglia. Neutralized by treatment with an IL-1 receptor (IL-1R1) antagonist during the repopulation phase impaired microglia proliferation. Furthermore, we found that conditional deletion of the IL-1R1 in microglia resulted in reduced numbers of microglia, but with an increased number of processes in the remaining microglia cells. Using the microglia ablation system we plan to investigate two questions related to these cells: First, we plan to start what are the microglia progenitor cells in the CNS. Secondly, we plan to keep mice depleted of microglia and investigate how lack of these cells affects the cognitive and behavioral phenotype of the mice. To analyze the role of IL-1 signaling on microglia development and function, we will use the mice lacking IL-1R1 in microglia. Furthermore, we will use a second mouse model developed in our lab that allows for the conditional deletion of the IL-1 receptor antagonist IL-1R2 in microglia, thus making these cells more sensitive to IL-1 signaling. Using these mouse strains, we will investigate the importance of IL-1 signaling in the development, maintenance, and function of microglia, including their role during inflammation and autoimmunity. In addition, we will test how deletion of IL-1 signaling in microglia (by deletion of IL-1R1) or enhancing this signaling (by deletion of IL-1R2) affects behavioral phenotype of the mice. IL-1alpha and IL-1beta are central players in CNS inflammation, but the impact of these cytokines on microglia during inflammation is not thoroughly investigated. To study CNS inflammation we will use two disease models, one for brain trauma where we will induce traumatic brain injury (TBI) in the mice. In the second autoimmune disease model, we will induce disease in a mouse model of multiple sclerosis termed experimental autoimmune encephalomyelitis (EAE). TBI and EAE will be induced in mice where microglia lack the expression of IL-1R1 and therefore cannot respond to IL1 signaling, or where these cells lack IL-1R2 and therefore hyper respond to such signaling. The studies presented in this proposal should help to better understand the role of microglia in vivo and the role they play in CNS inflammation and autoimmunity.

小胶质细胞是脑巨噬细胞，从胚胎卵黄囊中的早期红髓细胞前体中产生，并在血脑屏障形成之前迁移到脑间充质。这些细胞在大脑中播种并增殖，直到它们在中枢神经系统（CNS）中形成网格状分布，并在整个生命周期中保持不变。最近，我们培育了一个新的小鼠品系，可以有条件地消融成年小鼠的小胶质细胞。我们发现小胶质细胞区室在耗尽后一周内即可重建，这一过程完全依赖于中枢神经系统驻留细胞。通过基因表达谱分析，我们发现白介素 1 (IL-1) 受体在小胶质细胞再生过程中高表达。在再增殖阶段用 IL-1 受体 (IL-1R1) 拮抗剂治疗可中和损害小胶质细胞增殖。此外，我们发现小胶质细胞中IL-1R1的条件性缺失导致小胶质细胞数量减少，但剩余小胶质细胞中的突起数量增加。使用小胶质细胞消融系统，我们计划研究与这些细胞相关的两个问题：首先，我们计划开始研究中枢神经系统中的小胶质细胞祖细胞。其次，我们计划让小鼠体内的小胶质细胞消失，并研究这些细胞的缺乏如何影响小鼠的认知和行为表型。为了分析 IL-1 信号传导对小胶质细胞发育和功能的作用，我们将使用小胶质细胞中缺乏 IL-1R1 的小鼠。此外，我们将使用我们实验室开发的第二种小鼠模型，该模型允许有条件地删除小胶质细胞中的 IL-1 受体拮抗剂 IL-1R2，从而使这些细胞对 IL-1 信号传导更加敏感。使用这些小鼠品系，我们将研究 IL-1 信号传导在小胶质细胞发育、维持和功能中的重要性，包括它们在炎症和自身免疫过程中的作用。此外，我们将测试小胶质细胞中 IL-1 信号传导的缺失（通过删除 IL-1R1）或增强该信号传导（通过删除 IL-1R2）如何影响小鼠的行为表型。 IL-1α和IL-1β是中枢神经系统炎症的核心参与者，但这些细胞因子在炎症过程中对小胶质细胞的影响尚未得到彻底研究。为了研究中枢神经系统炎症，我们将使用两种疾病模型，一种用于脑外伤，我们将在小鼠中诱导创伤性脑损伤（TBI）。在第二种自身免疫性疾病模型中，我们将在多发性硬化症小鼠模型中诱导疾病，称为实验性自身免疫性脑脊髓炎（EAE）。如果小鼠的小胶质细胞缺乏 IL-1R1 的表达，因此无法对 IL1 信号传导作出反应，或者这些细胞缺乏 IL-1R2，因此对此类信号传导过度反应，则会诱导 TBI 和 EAE。该提案中提出的研究应有助于更好地了解小胶质细胞在体内的作用以及它们在中枢神经系统炎症和自身免疫中发挥的作用。