Interleukin-4 as a Novel therapy for Traumatic Brain Injury

 描述(由申请人提供)： 以脱髓鞘和轴突完整性为特征的脑白质损伤是创伤性脑损伤后长期感觉运动和认知功能障碍的重要原因。脑创伤后持续的促炎微环境被认为是阻碍少突胶质前体细胞(OPC)分化和成熟为髓鞘少突胶质细胞(OL)的潜在机制之一。越来越多的证据表明，不同功能表型的小胶质细胞/巨噬细胞在调节损伤的WM的炎症状态中起着重要作用，并最终影响WM的完整性。具体地说，“交替激活”的M2小胶质细胞对髓鞘再生和WM修复是必不可少的，因为它们可以解决局部炎症，清除破碎的髓鞘或细胞碎片，并提供促进OPC分化的营养因子。到目前为止，白介素4(IL-4)是小胶质细胞/巨噬细胞M2极化的最佳诱导剂；然而，它在西医中的小胶质细胞调节和脑外伤后的长期预后中的作用尚不清楚。我们的初步结果表明，通过鼻腔给药的IL-4纳米颗粒治疗后，增加了大脑中IL-4的水平，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的功能完整性，表现为有髓纤维动作电位传导幅度的增加。我们在体外发现，IL-4除了促进M2极化外，还在纳摩尔浓度下直接诱导原始OPC分化为成熟的OPC，这种作用是通过激活PPAR来实现的。在这个提案中，我们将重点放在新奇的动作上 研究IL-4对西医整体性的影响，并探讨其内在机制。我们将验证最重要的假设，即IL-4通过双重机制促进脑外伤后WM的完整性和长期神经功能恢复，因为它1)通过PPAR激活促进OPC的分化/成熟，2)增强小胶质细胞/巨噬细胞向有益的M2表型分化，这对脱髓鞘脑中的重新髓鞘形成和WM修复至关重要。测试的具体目标是：目的1：验证IL-4治疗后促进脑外伤后西医完整性和长期神经功能恢复的假说。在CCI后，IL-4将通过反复鼻腔给药进入大脑。评估的终点包括神经结果和各种西医完整性的标记物。目的：验证IL-4诱导OPC分化为成熟的OPC并通过激活PPAR促进轴突再髓鞘形成的假说。目的：验证IL-4促进小胶质细胞/巨噬细胞分化为消炎、促进组织修复的M2表型，并为有效的WM修复恢复“健康”微环境的假说。这项研究的成功将确定一种新的免疫疗法，以促进康复，从而改善遭受脑外伤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.