Macrophages protect against sensory axon loss in peripheral neuropathy

Sara Hakim, Aakanksha Jain, Stuart S. Adamson, Veselina Petrova, Jonathan Indajang, Hyoung Woo Kim, Riki Kawaguchi, Qing Wang, Elif S. Duran, Drew Nelson, Caitlin A. Greene, Jenae Rasmussen and Clifford J. Woolf ()
Additional contact information
Sara Hakim: Harvard Medical School
Aakanksha Jain: Boston Children’s Hospital
Stuart S. Adamson: Boston Children’s Hospital
Veselina Petrova: Boston Children’s Hospital
Jonathan Indajang: Boston Children’s Hospital
Hyoung Woo Kim: Boston Children’s Hospital
Riki Kawaguchi: University of California Los Angeles
Qing Wang: University of California Los Angeles
Elif S. Duran: Boston Children’s Hospital
Drew Nelson: Boston Children’s Hospital
Caitlin A. Greene: Boston Children’s Hospital
Jenae Rasmussen: Boston Children’s Hospital
Clifford J. Woolf: Harvard Medical School

Nature, 2025, vol. 640, issue 8057, 212-220

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

Date: 2025
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DOI: 10.1038/s41586-024-08535-1

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