Neuron-macrophage interactions in models of chemotherapy-induced peripheral neuropathy

化疗引起的周围神经病变模型中神经元-巨噬细胞的相互作用

• 批准号: 10673851
• 负责人: Wesley B Grueber
• 金额: $ 18.84万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-04 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673851
• 关键词: Affect; Afferent Neurons; Animal Model; Animals; Anti-Inflammatory Agents; Astrocytes; Biological Response Modifiers; Cells; Chemotherapy-induced peripheral neuropathy; Chronic; Clinic; Coculture Techniques; Data; Detection; Drosophila genus; Environment; Gene Targeting; Genes; Health; Host Defense; Human; Hypersensitivity; Immune; In Situ; In Vitro; Infiltration; Inflammation; Inflammatory; Knowledge; Link; Macrophage; Macrophage Activation; Maps; Mediating; Modeling; Molecular Profiling; Monitor; Morphology; Mus; Natural regeneration; Nature; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Nociception; Nociceptors; Paclitaxel; Pain; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral; Persons; Phenotype; Prevention; Prevention strategy; Proteins; Publishing; Recombinants; Research; Role; Sensory; Skin; Spinal Ganglia; Supplementation; System; Testing; Therapeutic; Time; Toxic effect; Treatment-related toxicity; Up-Regulation; Work; cell type; chemotherapy; clinically relevant; cytokine; debilitating pain; deep learning; effective therapy; extracellular; genetic manipulation; immunoregulation; in vivo; in vivo Model; innovation; mouse model; nerve injury; neuronal survival; neurotoxicity; neurotrophic factor; overexpression; pain sensitivity; painful neuropathy; prevent; sensory neuropathy; treatment strategy

Summary/Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) affects over 3 million people in the US without effective treatment. CIPN predominantly affects nociceptive (pain-sensing) nerve terminals, and often manifests as chronic debilitating pain in patients. Chemotherapy-induced inflammation strongly correlates with the onset of and persistent neuropathic pain. We propose to investigate peripheral interactions between macrophages, the most abundant immune cell type residing in skin, and nociceptive nerve terminals in CIPN. Molecular profiles of macrophages change continuously depending on their extracellular environment, allowing them to transition from resident to activated states. While pro- and anti-inflammatory activation of macrophages has been extensively studied, recent studies revealed many intermediate forms during the transition. How these are linked to pathological progression of nerves is still poorly understood, and we propose to fill this gap by using two complementary systems, Drosophila and mouse CIPN models. We will test the hypothesis that modulating macrophage activation could prevent peripheral sensory neuron hypersensitivity in CIPN. In our preliminary work, we established a Drosophila model to study neuron-macrophage interaction in vivo and found that macrophages activate and transition into different intermediate forms in a time-dependent manner that corresponds to nociceptive neuron phenotypes. Leveraging a single-cell quantitative approach using deep learning cell detection in situ, we found that expansion of activated macrophages peaks preceding morphological degeneration of neurons with a robust increase in selected pro- and anti-inflammatory genes. We further found a significant reduction in anti-inflammatory macrophages at a later stage, indicating an immune state switch between intermediate and late pathological stages. In search of genes that could modulate macrophage activation to promote neuronal health while not interfering with their roles in host defense, we identified mesencephalic astrocyte-derived neurotrophic factor, MANF, as a potential gene target for CIPN prevention. MANF is a potent regulator of immune activity, and its overexpression reduces the pro-inflammatory pathway and promotes activation of the anti-inflammatory pathway. In support, our preliminary results demonstrate that augmenting MANF prevents neuron phenotypes in Drosophila and mouse CIPN models, consistent with our hypothesis. We propose to characterize chemotherapy-induced macrophage profiles and investigate how MANF modulates macrophages to prevent neuronal toxicity in Drosophila in vivo and mouse neuron-macrophage co- culture CIPN models. Our proposal has a high potential to contribute to effective anti-inflammatory treatment for promoting neuronal health in CIPN.

摘要/摘要： 化学疗法引起的周围神经病（CIPN）在美国影响300万人而无效 治疗。 CIPN主要影响伤害性（疼痛）神经末端，并且通常表现为 长期使患者疼痛的疼痛。化学疗法诱导的炎症与开始的开始密切相关 和持续的神经性疼痛。我们建议研究巨噬细胞之间的外围相互作用， 大多数居住在皮肤中的免疫细胞类型，以及CIPN中的伤害性神经末端。分子曲线 巨噬细胞根据其细胞外环境不断变化，从而使其从 居民活化状态。尽管巨噬细胞的促和抗炎激活已广泛 研究，最近的研究揭示了过渡期间许多中间形式。这些如何链接到 神经的病理进展仍然很少了解，我们建议通过使用两个来填补这一空白 互补系统，果蝇和小鼠CIPN模型。我们将测试调节的假设 巨噬细胞激活可以防止CIPN中周围感觉神经元超敏反应。在我们的 初步工作，我们建立了一个果蝇模型，用于研究体内神经元巨噬细胞的相互作用并发现 巨噬细胞以时间依赖性的方式激活并过渡为不同的中间形式 对应于伤害性神经元表型。利用深处利用单细胞定量方法 学习细胞检测原位，我们发现活化巨噬细胞的膨胀在形态学之前的峰值 神经元的变性，在选定的促炎和抗炎基因中具有强大的增加。我们进一步发现 在后期，抗炎巨噬细胞显着降低，表明免疫状态开关 在中期和晚期病理阶段之间。寻找可以调节巨噬细胞的基因 激活以促进神经元健康而不干扰其在宿主防御中的角色，我们确定 中脑星形胶质细胞衍生的神经营养因子MANF，作为预防CIPN的潜在基因靶标。 MANF是免疫活动的有效调节剂，其过表达降低了促炎途径 并促进抗炎途径的激活。为了支持，我们的初步结果表明 增强MANF可防止果蝇和小鼠CIPN模型中的神经元表型，与我们的 假设。我们建议表征化学疗法诱导的巨噬细胞谱并研究MANF 调节巨噬细胞以防止果蝇和小鼠神经元巨噬细胞共同毒性毒性 培养CIPN模型。我们的建议具有很高的潜力，可以为有效的抗炎治疗做出贡献 促进CIPN的神经元健康。