New SCI research! Macrophages "rewrite" the "endgame" of diabetic complications?

With the continuous improvement of modern living standards, diabetes has gradually become a global health challenge, among which type 2 diabetes is closely related to obesity. Peripheral neuropathy (DPN), as a common complication of type 2 diabetes, not only causes sensory loss in patients, but may also cause neuropathic pain, significantly affecting their quality of life. Although the occurrence of DPN is related to factors such as hyperglycemia and dyslipidemia, the role of inflammation in the pathogenesis of DPN is still unclear.

Recently, a study published in Nature used a high-fat, high-fructose diet (HFHFD)-induced obese and prediabetic mouse model. This model can simulate the state of excessive eating and metabolic disorders in humans and is an ideal platform for studying the relationship between inflammation and DPN. Through this model, the study aims to systematically analyze the role of inflammation in the pathogenesis of DPN and further explore how immune cells are involved. This not only helps us understand the pathological mechanism of DPN more comprehensively, but also provides new ideas and directions for the development of more effective treatment strategies in the future.

Research Process

At the beginning of the study, the researchers fed the mice HFHFD for 3 months and conducted various tests. The results showed that the mice had reduced perception of heat pain after 3 months, but the reduction in skin nerve fibers was not obvious until 6 months later. Using advanced single-cell sequencing technology, the researchers found that CCR2 macrophages (a specific type of immune cell) entered the sciatic nerves of mice before nerve damage occurred. These cells are similar to macrophages triggered by injured nerves and show characteristics associated with neurodegeneration, even though the nerves are not obviously damaged at this time.

To explore the role of these macrophages in diabetic DPN, the researchers blocked CCR2 signaling through genetic and pharmacological methods. The results showed that inhibiting the aggregation of these macrophages aggravated the thermal hypoalgesia and skin nerve loss in mice. In addition, the lack of a protein called Lgals3 also exacerbated DPN symptoms, indicating that in obese prediabetic mice, these macrophages have a protective effect on peripheral nerves and help delay nerve degeneration through the Lgals3 protein.

Research Findings

1. Early manifestations of peripheral neuropathy

Mice fed a HFHFD showed sustained thermal hypoalgesia after 3 months, but a reduction in epidermal cutaneous nerve fiber density was not evident until 6 months, indicating that changes in sensory function occur before nerve damage occurs.

2. Role of Macrophages

CCR2 macrophages entered the sciatic nerves of mice before nerve damage occurred, and these cells were genetically similar to immune cells triggered by nerve damage and showed characteristics associated with neurodegeneration, suggesting that CCR2 macrophages may be involved in the early stages of neurodegeneration.

3. Neuroprotective effect of macrophage recruitment

When this aggregation was inhibited by genetically or pharmacologically blocking CCR2 signaling, the mice showed worsening neurological function, as evidenced by increased thermal hypoalgesia and accelerated skin denervation, suggesting that macrophage recruitment has a protective effect on peripheral nerves.

4. The role of Lgals3

When recruited macrophages lacked Lgals3, the mice's neurological function deteriorated, as evidenced by increased thermal hypoalgesia and accelerated skin denervation, suggesting that Gal-3 proteins play a neuroprotective role in macrophages, specifically in maintaining the health and function of nerve endings.

Future Outlook

This study provides a new perspective on the pathogenesis of diabetic peripheral neuropathy, emphasizing the core role of inflammation and macrophages in the progression of the disease. Future studies will further explore the complex interactions between immune cells and their effects on the health of neural tissue, while focusing on the specific mechanisms of action of neuroprotective molecules such as Lgals3, laying a theoretical foundation for the development of new treatment strategies. Treatments based on macrophage recruitment and Lgals3 signaling are expected to become a new way to slow or prevent diabetic peripheral neuropathy.

This study has unveiled the mystery behind the disease, not only deepening our understanding of the pathological mechanism, but also bringing hope to patients. With the deepening of research, we are expected to develop more accurate and effective treatments to help patients get rid of the pain and regain a healthy life. This is not only a scientific leap, but also a protection for human health. Let us look forward to these research results being transformed into practical clinical applications as soon as possible, bringing new life to countless patients and making life better!

References:

Hakim S, Jain A, Adamson SS, et al. Macrophages protect against sensory axon loss in peripheral neuropathy[J]. Nature (2025).