Mapping secretome-mediated interaction between paired neuron-macrophage single cells.
Mapping secretome-mediated interaction between paired neuron-macrophage single cells.
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绘制配对神经元与巨噬细胞单细胞之间分泌蛋白组介导的相互作用
DOI：
10.1073/pnas.2200944119
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发表时间：
2022-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
通过分泌因子的神经元-免疫相互作用是在中枢神经系统中形成复杂微环境的基础，该微环境可以改变生理和病理条件下的细胞功能和命运。为了评估神经元和免疫细胞之间的相互作用，我们使用抗体条形码微芯片同时从正常条件下配对的神经元-巨噬细胞和神经元-小胶质细胞单细胞和淀粉样β蛋白1-42（Aβ1-42）诱导的阿尔茨海默病模型中分析不同的分泌组，包括细胞因子，神经营养因子和神经元源性外泌体。结果揭示了神经元和免疫细胞之间的分泌介导的分泌组网络以及单神经元细胞分泌的复杂异质性。这些发现加深了我们对神经元和免疫细胞如何通过复杂的信号网络相互作用的理解，这可能有助于制定诊断策略。通过分泌因子的神经元-免疫相互作用对中枢神经系统中的复杂微环境有重要贡献，其可以改变生理和病理条件下的细胞功能和命运，这在单细胞水平上仍然很难表征。在本文中，使用空间图案化的抗体条形码微芯片，我们实现了12种不同分泌组的定位，包括细胞因子，神经营养因子（NF）和神经元来源的外泌体（NDEs），这些外泌体来自高通量，配对的单细胞（≥ 600），同时在正常条件下和用淀粉样β蛋白1-42（Aβ1-42）诱导的阿尔茨海默病（AD）模型。我们应用该平台来分析配对的神经元-巨噬细胞和神经元-小胶质细胞单细胞与人类细胞系的分泌谱。我们发现，成对的神经元-巨噬细胞相互作用会引发免疫反应并减弱神经元细胞的分泌，而神经元-小胶质细胞相互作用通常会导致相反的分泌结果。当神经元细胞被Aβ1-42蛋白诱导进入AD模型时，神经元-巨噬细胞和神经元-小胶质细胞相互作用均导致细胞因子和NDE增加以及NF减少。对AD患者血清的进一步分析表明，患者样本中的NDE显著高于对照组，验证了我们从相互作用试验中观察到的结果。此外，我们解决了以前未分化的异质性潜在的分泌单神经元细胞。我们发现NDE和NF分泌对彼此间的旁分泌信号的依赖性较低，并且神经元细胞在Aβ1-42分化后分泌物会减少。这项研究展示了配对神经元免疫单细胞的不同分泌组的映射，为理解神经元和免疫细胞如何通过复杂的分泌组网络相互作用提供了途径。
Neuron-immune interaction through secreted factors is the basis for forming the complex microenvironment in the central nervous system that could alter cell functionalities and fates in physiological and pathological conditions. To evaluate the interaction between neurons and immune cells, we used the antibody barcode microchip to profile different secretomes simultaneously from paired neuron–macrophage and neuron–microglia single cells under normal conditions and the amyloid beta protein 1-42 (Aβ1-42)–induced Alzheimer’s disease model, including cytokines, neurotrophic factors, and neuron-derived exosomes. The results uncovered the secretion-mediated secretome network between neurons and immune cells and the complex heterogeneity underlying the secretion from single-neuron cells. These findings deepen our understanding of how neurons and immune cells interact through the complex signaling network, which may help develop diagnostic strategies. Neuron-immune interaction through secreted factors contributes significantly to the complex microenvironment in the central nervous system that could alter cell functionalities and fates in both physiological and pathological conditions, which remains poorly characterized at the single-cell level. Herein, using a spatially patterned antibody barcode microchip, we realized the mapping of 12 different secretomes, covering cytokines, neurotrophic factors (NFs), and neuron-derived exosomes (NDEs) from high-throughput, paired single cells (≥ 600) simultaneously under normal conditions and an Alzheimer’s disease (AD) model induced with amyloid beta protein 1-42 (Aβ1–42). We applied the platform to analyze the secretion profiles from paired neuron–macrophage and neuron–microglia single cells with human cell lines. We found that pairwise neuron–macrophage interaction would trigger immune responses and attenuate neuron cells’ secretion, while neuron–microglia interaction generally results in opposite outcomes in secretion. When neuron cells are induced with Aβ1–42 protein into the AD model, both neuron–macrophage and neuron–microglia interactions lead to increased cytokines and NDEs and decreased NFs. Further analysis of AD patients’ serum showed that NDEs were significantly higher in patients’ samples than in the control group, validating our observation from the interaction assay. Furthermore, we resolved previously undifferentiated heterogeneity underlying the secretions from single-neuron cells. We found that the NDE and NF secretion was less dependent on the paracrine signaling between one another and that secretions from neuron cells would attenuate after differentiation with Aβ1–42. This study demonstrates the mapping of the different secretomes from paired neuron-immune single cells, providing avenues for understanding how neurons and immune cells interact through the complex secretome network.
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