Macrophages protect against sensory axon loss in peripheral neuropathy

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2674
• DOI: 10.1038/s41586-024-08535-1
• 发表日期: 2025-04-03
• 关键词: wallerian degeneration; mechanical allodynia; alzheimers-disease; nerve; microglia; mouse; trem2; activation; galectin-3; phenotype

摘要

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 galectin 3. Potentiating and sustaining early neuroprotective immune responses in patients could slow or prevent peripheral neuropathy.