The role of macrophage phenotype and age in spinal cord injury

 描述(申请人提供)：脊髓损伤(SCI)触发由巨噬细胞组成的异质神经炎性反应，具有加重组织损伤和促进伤口愈合和修复的潜力。这些巨噬细胞被鉴定为促炎、病理性的“M1”巨噬细胞或抗炎、交替激活、有利于修复的“M2”巨噬细胞。已发表的证据表明，推动M2巨噬细胞活化可促进脊髓损伤的恢复。然而，M2巨噬细胞修复作用的潜在机制尚不清楚。因此，开发临床上可行的、利用激活的巨噬细胞修复潜力的药理学干预措施仍然是一个关键的挑战，而不断变化的SCI人口统计加剧了这一挑战。近年来，老年人脊髓损伤的发病率有所增加，性别之间的脊髓损伤比例更加均等。本研究旨在探讨M2巨噬细胞介导的脊髓损伤修复机制，并探讨年龄、性别对脊髓损伤巨噬细胞活化的影响。目的1将通过使用缺乏精氨酸酶-1(Arg1)的巨噬细胞的基因工程小鼠和一种新发现的增加M2介导的精氨酸酶产生的治疗方法来确定精氨酸酶在M2巨噬细胞介导的脊髓损伤修复过程中的作用。平行的体内和体外脊髓损伤模型的神经毒性、轴突生长/死亡和重新髓鞘形成将检验M2巨噬细胞的作用依赖于Arg1产生的假设。目的：用2只不同年龄、不同性别的小鼠，研究这些生理因素对急性脊髓损伤巨噬细胞反应的影响。随着时间的推移，巨噬细胞的反应将使用新开发的聚焦基因图谱和流式细胞术技术进行评估。需要检验的假设是，老年男性M2巨噬细胞的激活会受到损害。在目标3中，将使用临床相关的小鼠脊髓损伤模型和新开发的免疫调节性脊髓损伤治疗方法来评估年龄和性别对M2巨噬细胞介导的脊髓损伤修复和恢复的影响。M2巨噬细胞的激活形式存在于大多数中枢神经系统病理中；因此，目前的工作具有重要意义，因为它有望在广泛的神经炎性疾病中产生广泛的翻译影响。这个项目在概念和技术上都是创新的。它将创造性地使用Arg1基因敲除小鼠和一种新的免疫调节剂。使用综合聚焦基因阵列方法研究年龄和性别对脊髓损伤后巨噬细胞反应的影响是一项新的研究。总的来说，拟议研究的完成将提高有关巨噬细胞生物学的科学知识，因为它特别与年龄和性别有关。这种知识将通过导致复杂的治疗策略来改进临床实践，其中包括性行为和 年龄在脊髓损伤治疗和康复方面的潜在影响。

 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a heterogeneous neuroinflammatory response consisting of macrophages with the potential to both aggravate tissue damage and promote wound healing and repair. These macrophages have been identified as pro-inflammatory, pathological "M1" macrophages or anti-inflammatory, alternatively activated, pro-reparative "M2" macrophages. There is published evidence that driving M2 macrophage activation improves SCI recovery. The mechanisms underlying the reparative effects of M2 macrophages, however, are not well understood. As a result, the development of clinically viable, pharmacological interventions that harness the reparative potential of activated macrophages remains a critical challenge that is compounded by a changing SCI demographic. The incidence of SCI among older individuals has increased in recent years with a more equal balance of SCI across sexes. The purpose of this proposal is to investigate the mechanisms of M2 macrophage-mediated SCI repair and determine the effects of age and sex on SCI macrophage activation. Aim 1 will determine the role of arginase in M2 macrophage-mediated SCI repair processes through the use of genetically engineered mice with macrophages that lack arginase-1 (Arg1) and a newly identified treatment that increases M2-mediated arginase production. Parallel in vivo and in vitro SCI models of neurotoxicity, axon growth/dieback, and remyelination will test the hypothesis that the effects of M2 macrophages are dependent upon Arg1 production. In Aim 2 mice of different ages and sex will be used to determine the effect of these physiological factors on the acute SCI macrophage response. The macrophage response over time will be evaluated using newly developed focused gene profiling and flow cytometry techniques. The hypothesis to be tested is that aged males will have impaired M2 macrophage activation. In Aim 3, the effect of age and sex on M2 macrophage-mediated SCI repair and recovery will be evaluated using a clinically relevant mouse SCI model and a newly developed immunomodulatory SCI treatment. Forms of M2 macrophage activation occur in most CNS pathologies; therefore the current work is significant because it is expected to have broad translational impact on a wide range of neuroinflammatory conditions. This project is both conceptually and technically innovative. It will employ creative use of Arg1 knockout mice and a novel immunomodulatory agent. The investigation of the effects of age and sex on the macrophage response to SCI using a comprehensive focused gene array approach is novel. Collectively, the completion of the proposed research will improve scientific knowledge regarding macrophage biology as it specifically relates to age and sex. This knowledge will improve clinical practice by leading to sophistication of treatment strategies that include sex and age as potential influences in the context of SCI treatment and recovery.