Interleukin-4 as a Novel therapy for Traumatic Brain Injury

 描述（由申请人提供）： 白色物质（White matter，WM）损伤是创伤性脑损伤（traumatic brain injury，TBI）后长期感觉运动和认知功能障碍的重要原因。TBI后持续的促炎微环境被认为是阻碍少突胶质细胞前体细胞（OPC）分化和成熟为髓鞘少突胶质细胞（OL）的一种潜在机制。越来越多的证据表明，不同的功能表型的小胶质细胞/巨噬细胞的损伤WM的炎症状态的调节，并最终影响WM的完整性作出了贡献。具体而言，“交替激活”的M2小胶质细胞对于髓鞘再生和WM修复是必不可少的，因为它们解决局部炎症，清除破裂的髓鞘或细胞碎片，并提供促进OPC分化的营养因子。 迄今为止，白细胞介素-4（IL-4）是小胶质细胞/巨噬细胞M2极化的最佳表征诱导剂;然而，其在WM中的小胶质细胞调节和TBI后的长期结局中的作用尚不清楚。我们的初步结果表明，通过鼻内递送IL-4纳米颗粒后处理增加了脑中的IL-4水平，并改善了受控皮质撞击（CCI）后的长期神经功能。值得注意的是，IL-4治疗增强了CCI后WM功能的完整性，如有髓纤维中动作电位传导幅度增加所示。我们已经在体外发现，除了促进M2极化，IL-4在纳摩尔浓度下直接诱导原代OPCs分化为成熟OL，并且IL-4对OPCs的这种作用是通过激活PPAR γ介导的。 在这个建议中，我们将重点放在小说的行动 IL-4对WM完整性的影响，并探讨其可能的作用机制。我们将测试总体假设，即IL-4通过双重机制促进TBI后的WM完整性和长期神经恢复，因为它1）通过PPAR γ活化促进OPC分化/成熟和2）增强小胶质细胞/巨噬细胞向有益的M2表型极化，这对于脱髓鞘脑中的髓鞘再生和WM修复是必需的。待测试的具体目的是：目的1：测试IL-4治疗后增强WM完整性和TBI后长期神经恢复的假设。CCI后，IL-4将通过重复鼻内给药递送至脑中。评估终点包括神经学结局和WM完整性的各种标志物。目的2：验证IL-4诱导OPC分化为成熟OL并通过激活PPAR γ促进轴突髓鞘再生的假设。目标3：检验IL-4增强小胶质细胞/巨噬细胞极化为炎症消退、组织修复增强的M2表型并恢复“健康”微环境以进行有效WM修复的假设。这项研究的成功将确定一种新的免疫疗法，以加强康复，从而提高患有TBI的退伍军人的生活质量。

 DESCRIPTION (provided by applicant): White matter (WM) injury, characterized by demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor and cognitive deficits after traumatic brain injury (TBI). A persistent pro-inflammatory microenvironment after TBI is considered one underlying mechanism that hinders oligodendrocyte precursor cell (OPCs) differentiation and maturation into myelinating oligodendrocytes (OLs). Accumulating evidence suggests that the different functional phenotypes of microglia/macrophages contribute considerably to the regulation of inflammatory status of injured WM and ultimately impact the WM integrity. Specifically, "alternatively activated" M2 microglia are essential for remyelination and WM repair because they resolve local inflammation, clear broken myelin sheath or cellular debris, and provide trophic factors that promote OPC differentiation. Interleukin-4 (IL-4) is thus far the best characterized inducer for M2 polarization of microglia/macrophages; however, its role in microglia regulation in WM and long term outcomes after TBI is not known. Our preliminary results show that post-treatment with IL-4 nanoparticle through intranasal delivery increased IL-4 levels in the brain and improved long-term neurological functions after controlled cortical impact (CCI). Remarkably, IL-4 treatment enhanced post-CCI WM functional integrity, as shown by increased amplitude of action potential conduction in myelinated fibers. We have found in vitro that in addition to promoting M2 polarization, IL-4 directly induces the differentiation of primary OPCs into mature OLs at nanomolar concentrations and that this effect of IL-4 on OPCs is mediated through the activation of PPAR. In this proposal, we will focus on the novel action of IL-4 on WM integrity and explore the underlying mechanisms. We will test the overarching hypothesis that IL-4 promotes WM integrity and long-term neurological recovery after TBI by dual mechanisms, in that it 1) promotes OPC differentiation/ maturation via PPAR activation and 2) potentiates microglia/macrophage polarization toward the beneficial M2 phenotype, which is essential for remyelination and WM repair in demyelinating brains. The Specific Aims to be tested are: Aim 1: Test the hypothesis that IL-4 post-treatment enhances WM integrity and long-term neurological recovery after TBI. IL-4 will be delivered into the brain by repeated intranasal administrations after CCI. The endpoints for assessment include neurological outcomes and various markers for WM integrity. Aim 2: Test the hypothesis that IL-4 induces OPC differentiation into mature OLs and promotes axonal remyelination via PPAR activation. Aim 3: Test the hypothesis that IL-4 potentiates microglia/macrophage polarization into the inflammation-resolving, tissue repair-enhancing M2 phenotype and restores a "healthy" microenvironment for efficient WM repair. The success of this study will identify a novel immunotherapy to enhance rehabilitation and therefore improve quality of life for veterans suffering TBI.