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Papers of the Week

Papers: 10 Feb 2024 - 16 Feb 2024

2024 Jan 30



Macrophages protect against sensory axon degeneration in diabetic neuropathy.


Hakim S, Jain A, Petrova V, Indajang J, Kawaguchi R, Wang Q, Duran ES, Nelson D, Adamson SS, Greene C, Woolf CJ


Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, causing sensory loss and debilitating neuropathic pain . Although the onset and progression of DPN have been linked with dyslipidemia and hyperglycemia , the contribution of inflammation in the pathogenesis of DPN has not been investigated. Here, we use a High Fat High Fructose Diet (HFHFD) to model DPN and the diabetic metabolic syndrome in mice. Diabetic mice develop persistent heat hypoalgesia after three months, but a reduction in epidermal skin innervation only manifests at 6 months. Using single-cell sequencing, we find that CCR2+ macrophages infiltrate the sciatic nerves of diabetic mice well before axonal degeneration is detectable. We show that these infiltrating macrophages share gene expression similarities with nerve crush-induced macrophages and express neurodegeneration-associated microglia marker genes although there is no axon loss or demyelination. Inhibiting this macrophage recruitment in diabetic mice by genetically or pharmacologically blocking CCR2 signaling results in a more severe heat hypoalgesia and accelerated skin denervation. These findings reveal a novel neuroprotective recruitment of macrophages into peripheral nerves of diabetic mice that delays the onset of terminal axonal degeneration, thereby reducing sensory loss. Potentiating and sustaining this early neuroprotective immune response in patients represents, therefore, a potential means to reduce or prevent DPN.