Macrophages to the rescue: the surprising guardians of nerve health in diabetes

Aims: This study investigates the role of macrophages in protecting against sensory axon loss in a mouse mode of peripheral neuropathy associated with prediabetes and obesity.

Methods: A high-fat, high-fructose diet (HFHFD) was used to induce obesity and prediabetes in mice, leading to sensory deficits characteristic of diabetic peripheral neuropathy (DPN). Single-cell sequencing and flow cytometry were employed to analyse immune cell infiltration in the sciatic nerve. Genetic and pharmacological approaches, including C-C chemokine receptor type 2 (CCR2) knockout and galectin-3 (Lgals3) deletion, were used to investigate the role of recruited macrophages.

Results: Macrophages infiltrated sciatic nerves early in disease progression, prior to detectable axon degeneration. Blocking CCR2-dependent macrophage recruitment exacerbated sensory deficits and accelerated axonal loss, while macrophages expressing galectin-3 were found to delay axon degeneration.

Conclusions: The study provides compelling evidence that macrophages recruited to peripheral nerves in prediabetes play a protective role in delaying sensory axon loss.

Comments: This study represents a paradigm shift in our understanding of neuroimmune interactions in diabetic peripheral neuropathy. Traditionally, inflammation in DPN has been considered a driver of pathology, but this research highlights a neuroprotective role for macrophages. By employing single-cell transcriptomics and in vivo genetic manipulations, the authors uncover a complex and dynamic immune response that may be harnessed therapeutically. A major strength of the study lies in its use of a prediabetic mouse model, which better mirrors human disease progression than conventional models of overt diabetes. The identification of galectin-3 as a key neuroprotective factor is particularly intriguing, as it suggests potential therapeutic targets to modulate immune responses in neuropathy. Additionally, the comparison of recruited macrophages in DPN to those in nerve injury models provides valuable insights into shared repair mechanisms across different forms of axonal damage. However, some limitations must be acknowledged. While the study establishes macrophage recruitment as beneficial, the precise mechanisms by which galectin-3 exerts its protective effects remain unclear. Future work should explore whether direct modulation of galectin-3 or macrophage activity could be a viable therapeutic strategy in human patients. Looking ahead, this research opens new avenues for targeting immune responses in neurodegenerative conditions. The findings suggest that rather than broadly suppressing inflammation, therapies should aim to enhance beneficial immune processes. Ultimately, this study challenges long-standing assumptions about inflammation in DPN and provides a compelling case for macrophage-targeted therapies. The work represents an important step toward a more nuanced understanding of immune contributions to neurodegeneration and neuroprotection.

Ali Jaafar

Reference: Hakim S, Jain A, Adamson SS, Petrova V, Indajang J, Kim HW, Kawaguchi R, Wang Q, Duran ES, Nelson D, Greene CA, Rasmussen J, Woolf CJ. Macrophages protect against sensory axon loss in peripheral neuropathy. Nature. 2025 Feb 12. doi: 10.1038/s41586-024-08535-1. Epub ahead of print. PMID: 39939762.

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