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

总结/摘要： 化疗引起的周围神经病变（CIPN）影响了美国超过300万人， 治疗CIPN主要影响伤害性（疼痛感测）神经末梢，并且通常表现为 患者的慢性衰弱性疼痛。化疗诱导的炎症与肿瘤的发生密切相关。 和持续的神经性疼痛。我们建议研究巨噬细胞， 最丰富的免疫细胞类型存在于皮肤和CIPN中的伤害感受神经末梢。分子概况 巨噬细胞不断变化，这取决于它们的细胞外环境，使它们从 居民到激活状态。虽然巨噬细胞的促炎和抗炎激活已经被广泛应用于 最近的研究揭示了过渡期间的许多中间形式。这些是如何与 神经的病理进展仍然知之甚少，我们建议通过使用两个 互补系统，果蝇和小鼠CIPN模型。我们将检验调节 巨噬细胞活化可防止CIPN中外周感觉神经元的超敏反应。在我们 初步工作，我们建立了一个果蝇模型，研究体内神经元-巨噬细胞相互作用，发现 巨噬细胞以时间依赖性方式激活并转变为不同的中间形式， 对应于伤害感受神经元表型。利用单细胞定量方法， 学习原位细胞检测，我们发现活化的巨噬细胞的扩增在形态学之前达到峰值， 神经元的退化与选定的促炎和抗炎基因的强劲增长。我们进一步发现 后期抗炎巨噬细胞显著减少，表明免疫状态转换 中间和晚期病理阶段之间。寻找能够调节巨噬细胞的基因 激活，以促进神经元的健康，同时不干扰其在宿主防御中的作用，我们确定 中脑星形胶质细胞源性神经营养因子（MANF）作为CIPN预防的潜在基因靶点。 MANF是一种有效的免疫活性调节剂，其过表达减少了促炎途径 并促进抗炎途径的激活。作为支持，我们的初步结果表明， 在果蝇和小鼠CIPN模型中，增强MANF可以防止神经元表型，这与我们的研究结果一致。 假说.我们建议描述化疗诱导的巨噬细胞的特征，并研究MANF 调节巨噬细胞，以防止果蝇体内神经元毒性和小鼠神经元-巨噬细胞共 文化CIPN模型。我们的建议具有很高的潜力，有助于有效的抗炎治疗， 促进CIPN中的神经元健康。

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.