自噬-趋化因子交联介导星形胶质细胞-神经元交流参与神经病理性疼痛的机制研究

Neuropathic pain complaints，although common, are generally poorly served by existing therapies. It has been found that astrocyte - neuron interaction plays an important role in the regulation of neuropathic pain. More and more studies have shown that chemokines are involved in astrocyte-neuron communication and neuropathic pain. Autophagy maintains the homeostasis of the nervous system, but its effect and mechanism in the regulation of pain needs further studying. Our preliminary studies found that there was a strong correlation between autophagy and neuropathic pain, and pain was alleviated by inducing autophagy and aggravated by inhibiting autophagy. Autophagy flow in spinal cord was impaired in the late stage of neuropathic pain, which mainly concentrated in astrocytes. The level of chemokine (C-C motif) ligand 7 (CCL7) was increased after autophagy inhibited. Therefore, we formulate the following hypothesis: in the neuropathic pain model induced by peripheral nerve injury, the impairment of autophagy can mediate astrocyte - neuron interaction through regulating the level of chemokines, and then participate in the regulation of neuropathic pain. Combined animal experiments with cell experiments, this study will focus on following two aspects: firstly, which interneurons are regulated by autophagy in astrocytes in the late stage of neuropathic pain; secondly, which chemokines play a significant role and its mechanism in the process of autophagy regulating astrocyte-neuron interaction. This study provides a support mechanism for autophagy participation in the regulation of glial cell-neuron network, and a potential target for neuropathic pain treatment.

神经病理性疼痛发病率高，机制复杂，疗效欠佳。星形胶质细胞-神经元交互作用在神经病理性疼痛调控中发挥关键作用。趋化因子参与星形胶质细胞-神经元交流以及神经病理性疼痛调控。自噬维持神经系统稳态，但在疼痛调控中的作用和机制有待研究。我们预实验发现：自噬与神经病理性疼痛密切相关，诱导自噬减轻疼痛，抑制自噬加重疼痛；疼痛晚期脊髓组织中，自噬流受损，集中于星形胶质细胞；抑制自噬提高趋化因子CCL7水平。因此，我们提出以下假说：外周神经损伤诱导神经病理性疼痛模型中，自噬受损可以通过调节趋化因子水平而介导星形胶质细胞-神经元交互作用，参与神经病理性疼痛调控。我们将结合动物实验和细胞实验，一是研究疼痛晚期星形胶质细胞自噬受损调控哪类中间神经元；二是研究哪类趋化因子在自噬调控星形胶质细胞-神经元交互作用中发挥关键作用及其机制。此研究为自噬参与胶质细胞-神经元调控提供机制支持，为神经病理性疼痛治疗提供潜在靶点。

神经病理性疼痛发病机制复杂，涉及神经元、胶质细胞、免疫细胞等多种细胞类型。星形胶质细胞是中枢神经系统数量最多的胶质细胞，维持神经系统稳态和突触可塑性。星形胶质细胞-神经元交流在神经病理性疼痛发生发展中发挥关键作用，但相关机制需要深入研究。自噬是进化保守的过程，参与神经系统多种生理病理过程。本课题以神经病理性疼痛为主线，围绕自噬变化对星形胶质细胞-神经元交流的影响及相关机制进行研究，主要研究内容有两个方面：一是星形胶质细胞自噬变化对趋化因子水平影响及其相关机制；二是星形胶质细胞自噬变化对神经元活性氧应激的影响及其相关机制。课题组研究发现神经病理性疼痛水平与自噬诱导与自噬抑制药物剂量之间存在相关性；抑制自噬增加星形胶质细胞趋化因子CCL7水平，这主要由抑制自噬后星形胶质细胞JNK、NF-κB通路活化介导的；抑制自噬降低星形胶质细胞来源的谷胱甘肽水平并降低其对神经元活性氧应激的保护作用降低；NRF2通路参与调节星形胶质细胞来源的谷胱甘肽水平，活化NRF2通路可以部分逆转星形胶质细胞自噬损伤引起的谷胱甘肽水平降低，并且增加其对神经元活性氧应激保护作用。此研究提高了人们对神经病理性疼痛的认识水平，也为其治疗提供了潜在靶点，具有临床转化及应用价值。

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