Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor–β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor–1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal–regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.

中文翻译：

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卵泡抑素通过伤害性神经元中的 IGF1R 信号传导驱动小鼠神经性疼痛


神经性疼痛是一种缺乏有效治疗的使人衰弱的慢性疾病。细胞因子和趋化因子介导的神经炎症在其发病机制中的作用已得到充分证明。卵泡抑素 （FST） 是一种分泌蛋白，已知可拮抗转化生长因子-β （TGF-β） 超家族中细胞因子的生物活性。FST 与神经性疼痛的参与及其潜在机制在很大程度上仍是未知的。在这里，我们报道了小鼠脊神经结扎 （SNL） 后 FST 在 A 纤维感觉神经元中上调。FST 的抑制或缺失减轻了神经性疼痛，并降低了 SNL 诱导的伤害性神经元过度兴奋。相反，重组 FST 的鞘内或足底内注射，或在背根神经节 （DRG） 神经元中过表达 FST，诱导疼痛超敏反应。此外，外源性 FST 增加了伤害性神经元的神经元兴奋性。生物膜干涉测量法 （BLI） 测定和免疫共沉淀 （co-IP） 显示 FST 与胰岛素样生长因子-1 受体 （IGF1R） 直接结合，IGF1R 抑制降低了 FST 诱导的细胞外信号调节激酶 （ERK） 和蛋白激酶 B （AKT） 的激活，以及神经元过度兴奋。进一步的 co-IP 分析显示，FST 的 N 末端结构域对 IGF1R 表现出最高的亲和力，阻断与 FST 衍生肽的这种相互作用减弱了 Nav1.7 介导的神经元过度兴奋和 SNL 后的神经性疼痛。此外，FST 通过 IGF1R 增强了人 DRG 神经元的神经元兴奋性。总的来说，我们的研究结果表明，从 A 纤维神经元释放的 FST 增强了 Nav1。通过与 IGF1R 结合，7 介导的伤害性神经元过度兴奋，使其成为神经性疼痛治疗的潜在靶点。