Neuropeptide Lacking in Diabetics Promotes Wound Healing

The innate immune response is known to impact early stages of wound repair, with the role of some sensory neurons, including nociceptors, established as immunoregulators. However, the extent of the interaction between the immune and nervous systems is not well understood.

In a new report, researchers from the Australian Regenerative Medicine Institute (ARMI) at Monash University, have found that a neuropeptide lacking in patients with diabetes promotes wound healing by acting on specific types of immune cells. They published their study, “CGRP sensory neurons promote tissue healing via neutrophils and macrophages” in the latest issue of Nature.

The impacts of poor wound healing ability are widespread, so understanding the mechanisms underlying how the process occurs will have a broad impact for individuals and healthcare globally.

“In adults with diabetes alone—where poor blood flow can lead to quickly worsening wounds that are often very slow or impossible to heal—the lifetime risk of developing a diabetic foot ulcer (DFU), the most common diabetes-related wound, is 20–35 percent and this number is rising with increased longevity and medical complexity of people with diabetes,” stated lead author, Yen-Zhen Lu, PhD, an investigator at ARMI.

Nociceptors—neurons that sense pain, tissue damage, and inflammation, among other functions—respond to wounds by producing a neuropeptide called calcitonin gene-related peptide (CGRP). “Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide CGRP during the healing process,” the authors wrote. Immune cell response in neutrophils, monocytes, and macrophages are modified to encourage active repair in the region.

Individuals with diseases like diabetes or elderly people have reduced production of CGRP, leading to poor, inefficient, or incomplete wound healing. The new study explores the impact of CGRP alone by introducing it into diabetic mice as well as mice without nociceptors. “Delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration,” the authors wrote. “Remarkably, this neuropeptide acts on immune cells to control them, facilitating tissue healing after injury,” added co-author Mikaël Martino, PhD, associate professor, ARMI.

These results could have a significant impact on regenerative medicine and wound care, especially for people with chronic conditions resulting in a reduced ability to heal wounds. Martino said his team’s findings “could transform regenerative medicine, because it sheds light on the crucial role of sensory neurons in orchestrating the repair and regeneration of tissues, offering promising implications for improving patient outcomes.” Future therapies developed to address wound care can progress from symptom management to addressing and assisting with treating early stages of wound healing.

“This study has uncovered significant implications for advancing our understanding of the tissue healing process after acute injury,” Martino concluded. “Harnessing the potential of this neuro-immuno-regenerative axis opens new avenues for effective therapies, whether as standalone treatments or in combination with existing therapeutic approaches.”