美国波士顿儿童医院Clifford J. Woolf小组发现了巨噬细胞保护周围神经病变的感觉轴突损失。相关论文于2025年2月12日发表在《自然》杂志上。

本研究采用高脂肪、高果糖饮食（HFHFD）诱导肥胖和糖尿病前期代谢变化，研究周围神经病变的发病。饲喂HFHFD的小鼠在3个月后出现持续性热痛觉减退，但表皮皮肤神经纤维密度仅在6个月时出现减少。通过单细胞测序，该团队发现CCR2⁺巨噬细胞在HFHFD喂养小鼠的坐骨神经轴突变性检测到之前就已经浸润。这些浸润性巨噬细胞与神经基质诱导的巨噬细胞具有相似的基因表达，并表达神经变性相关的小胶质标记基因，尽管没有轴突丢失或脱髓鞘。

通过基因或药物阻断CCR2信号传导抑制巨噬细胞募集，导致更严重的热痛觉减退和加速皮肤去神经，募集巨噬细胞中表达的Lgals3基因的缺失也是如。因此，巨噬细胞募集到肥胖糖尿病前期小鼠的周围神经具有神经保护作用，通过聚集素延缓末梢感觉轴突变性。增强和维持患者早期的神经保护性免疫反应可以减缓或预防周围神经病变。

据了解，周围神经病变是2型糖尿病的常见并发症，与肥胖、导管感觉丧失以及部分患者的神经性疼痛密切相关。虽然糖尿病周围神经病变的发生和发展与血脂异常和高血糖有关，但炎症对周围神经病变发病机制的贡献尚未得到研究。

附：英文原文

Title: Macrophages protect against sensory axon loss in peripheral neuropathy

Author: Hakim, Sara, Jain, Aakanksha, Adamson, Stuart S., Petrova, Veselina, Indajang, Jonathan, Kim, Hyoung Woo, Kawaguchi, Riki, Wang, Qing, Duran, Elif S., Nelson, Drew, Greene, Caitlin A., Rasmussen, Jenae, Woolf, Clifford J.

Issue&Volume: 2025-02-12

Abstract: Peripheral neuropathy is a common complication of type 2 diabetes, which is strongly associated with obesity1, causing sensory loss and, in some patients, neuropathic pain2,3. Although the onset and progression of diabetic peripheral neuropathy is linked with dyslipidaemia and hyperglycaemia4, the contribution of inflammation to peripheral neuropathy pathogenesis has not been investigated. Here we used a high-fat, high-fructose diet (HFHFD), which induces obesity and prediabetic metabolic changes, to study the onset of peripheral neuropathy. Mice fed the HFHFD developed persistent heat hypoalgesia after 3 months, but a reduction in epidermal skin nerve fibre density manifested only at 6 months. Using single-cell sequencing, we found that CCR2⁺ macrophages infiltrate the sciatic nerves of HFHFD-fed mice well before axonal degeneration is detectable. These infiltrating macrophages share gene expression similarities with nerve-crush-induced macrophages5 and express neurodegeneration-associated microglial marker genes6, although there is no axon loss or demyelination. Inhibiting the macrophage recruitment by genetically or pharmacologically blocking CCR2 signalling resulted in more severe heat hypoalgesia and accelerated skin denervation, as did deletion of Lgals3, a gene expressed in recruited macrophages. Recruitment of macrophages into the peripheral nerves of obese prediabetic mice is, therefore, neuroprotective, delaying terminal sensory axon degeneration by means of galectin3. Potentiating and sustaining early neuroprotective immune responses in patients could slow or prevent peripheral neuropathy.

DOI: 10.1038/s41586-024-08535-1

Source: https://www.nature.com/articles/s41586-024-08535-1