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Macrophages protect against sensory axon loss in peripheral neuropathy

Author

Listed:
  • Sara Hakim

    (Harvard Medical School
    Boston Children’s Hospital)

  • 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
    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
    Boston Children’s Hospital)

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.

Suggested Citation

  • 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, 2025. "Macrophages protect against sensory axon loss in peripheral neuropathy," Nature, Nature, vol. 640(8057), pages 212-220, April.
  • Handle: RePEc:nat:nature:v:640:y:2025:i:8057:d:10.1038_s41586-024-08535-1
    DOI: 10.1038/s41586-024-08535-1
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