Targeting peripheral CCR2 macrophages in traumatic brain injury

描述（由申请人提供）：在美国，每年至少有170万人遭受创伤性脑损伤（TBI）；在美国所有与伤害有关的死亡中，有33%是由它造成的。估计有320万至530万人患有创伤性脑损伤造成的长期身体、认知和心理健康残疾，每年的直接和间接费用估计超过800亿美元。此外，这些发现与海外部署的退伍军人的创伤性脑损伤病例的迅速增加有关。现在人们认识到TBI是一个过程，而不是一个事件。有新的证据表明，这一过程可导致多种神经退行性疾病。在临床上，脑外伤是阿尔茨海默病和痴呆症发生的最重要的环境危险因素之一。然而，这种关联的分子机制尚未确定。新出现的证据表明，由于非特异性继发性或“旁观者”损伤主要未受影响的大脑区域，特别是海马形成，神经炎症可能在tbi诱导的神经病理学中起关键作用。中枢神经系统炎症反应的主要效应器是小胶质细胞，它作为中枢神经系统的常驻组织巨噬细胞。最近在正电子发射断层扫描配体成像方面的研究表明，创伤性脑损伤的长期幸存者在初始创伤后的数年内仍持续激活这种先天反应。特别令人困惑的是，无法可靠地区分常驻巨噬细胞（小胶质细胞）作用与损伤诱导的外周单核细胞/巨噬细胞浸润，因为在激活后，两者在功能和外观上都是无法区分的。因此，这些浸润细胞在与TBI相关的神经病理学中的作用仍不清楚。目的1：将确定外周来源的CCR2阳性巨噬细胞在脑外伤后的时间相关积累。使用控制性皮质冲击法对CX3CR1+/GFPCCR2+/RFP报告小鼠进行脑损伤诱导，这允许描述常驻和外周固有免疫细胞。我们将通过损伤后急性到慢性期的综合时间过程来研究外周巨噬细胞的积累及其在大脑中的炎症谱。初步研究表明，该模型诱导海马依赖性认知功能障碍，CCR2细胞浸润显著增加，并伴随促炎介质的产生。这一目标的结果将研究TBI与外周巨噬细胞积累及其炎症特征之间的关系。目的2：将确定靶向CCR2的药理学效果，以改善tbi诱导的促炎反应和最终的认知功能障碍。初步数据表明，使用一种新型i期拮抗剂靶向CCR2阳性巨噬细胞可显著减少损伤后外周巨噬细胞的积累。此外，这种治疗模式显著降低了多种促炎/神经毒性反应的表达。由于Aim将定义Aim 2的治疗基础，我们将扩展治疗模式以覆盖外周巨噬细胞浸润的峰值，以检查这种治疗对改善创伤后慢性期tbi诱导的海马依赖性认知功能障碍的影响。

DESCRIPTION (provided by applicant): Each year in the United States, at least 1.7 million people suffer traumatic brain injury (TBI); it is a contributing factor in 33% of all injury-relate US deaths. An estimated 3.2 to 5.3 million people live with the long-term physical, cognitive, and psychological health disabilities of TBI, with annual direct and indirect costs estimated at over $80 billion. Moreover, these findings are compounded by the rapid increase in TBI cases from returning veterans of overseas deployments. It is now being recognized that TBI is a process, not an event. There is emerging evidence that this process can lead to multiple neurodegenerative disorders. Clinically, TBI is one of the most powerful environmental risk factors for the development of Alzheimer's disease and dementia. However, a molecular mechanism for this association has not been identified. Emerging evidence suggests that neuroinflammation may play a pivotal role in TBI-induced neuropathology as a result of non-specific secondary or 'bystander' injury to primarily unaffected brain regions, notably the hippocampal formation. The primary effectors of CNS neuroinflammatory response are the microglia, which act as the CNS' resident tissue macrophage. Recent work in positron emission tomography ligand imaging has shown that long-term survivors of TBI have persistent activation of this innate response for years following the initial trauma. Particularly confounding to this phenomenon is the inability to reliably distinguish resident macrophage (microglia) effects versus injury-induced infiltration of peripheral monocytes/macrophages, as upon activation, each is phenotypically indistinguishable in function and appearance. Therefore the role of these infiltrating cells in the neuropathology associated with TBI remains unclear. Aim 1: Will determine the time-related accumulation of peripherally derived CCR2 positive macrophages in the brain following TBI. Brain injury will be induced using the controlled cortical impact method on CX3CR1+/GFPCCR2+/RFP reporter mice, which allow the delineation of resident versus peripheral innate immune cells. We will examine peripheral macrophage accumulation and their inflammatory profile in the brain through a comprehensive time course spanning the acute through chronic phases following injury. Preliminary studies indicate that this model induces hippocampal-dependent cognitive dysfunction, a marked increase in CCR2 cell infiltration, as well as concomitant production of pro-inflammatory mediators. Results from this aim will examine the relationship between TBI and accumulation of peripheral macrophages and their inflammatory profile across time. Aim 2: Will determine the efficacy of targeting CCR2 pharmacologically to ameliorate TBI-induced pro- inflammatory response and ultimately cognitive dysfunction. Preliminary data suggest that targeting CCR2 positive macrophages using a novel phase-I antagonist significantly depletes peripheral macrophage accumulation following injury. Moreover, this treatment paradigm significantly decreased the expression of multiple pro-inflammatory/neurotoxic responses. As Aim will define the therapeutic basis for Aim 2, we will extend treatment paradigm to cover the peak of peripheral macrophage infiltration to examine the effects this treatment has on ameliorating TBI-induced hippocampal dependent cognitive dysfunction in the chronic phase following injury.