Skin-Resident Immune Cells Drive Neuropathic Pain in Diabetes

In experimental models of diabetes, Northwestern Medicine scientists have discovered that a specialized group of skin-resident immune cells drive neuropathic pain through sex-dependent signaling pathways, according to a recent study published in The Journal of Clinical Investigation.

The findings suggest that therapeutically targeting these cells could be an effective approach for treating neuropathic pain in patients with diabetes, according to Daniela Maria Menichella, MD, PhD, ’08, ’11 GME, associate professor in the Ken and Ruthe Davee Department of Neurology’s Division of Neuromuscular Disease and senior author of the study.

“Our understanding of peripheral neuropathy in diabetes is not only about nerve damage, but also about how the ecosystem in the skin changes and how diabetes alters the communication between non-neuronal immune cells and nerves in the skin. Targeting immune cells in the skin could therefore be a valid therapeutic option to restore nerve health and alleviate pain in diabetes,” said Menichella, who is also an associate professor of Pharmacology.

Diabetic neuropathy occurs when high blood sugar levels injure nerves throughout the body. Diabetic neuropathy most commonly damages nerves in the legs and feet, causing pain, numbness, and muscle weakness, but can also impact the digestive system, urinary tract, blood vessels and the heart. Current treatment involves managing a patient’s blood sugar levels and prescribing additional medications and therapies to treat related symptoms.

Neuropathic pain in patients with diabetes arises from the hyperexcitability of nociceptor neurons in the dorsal root ganglia — clusters of nerve cells throughout the spinal cord that transmit sensory information from the body to the central nervous system.

The underlying molecular mechanisms driving this persistent neuropathic pain have remained poorly understood, however emerging evidence suggests that non-neuronal skin cells may affect nociceptor neuronal function.

In the study, the scientists discovered that Langerhans cells — tissue-resident immune cells located throughout the epidermis, the outermost layer of the skin — contribute to neuropathic pain in diabetic neuropathy through unique neuroimmune signaling pathways.

The scientists used a multi-pronged experimental approach, including a high-fat diet mouse model, transgenic Langerhans cells ablation, behavioral assays, human skin biopsies, and single-cell RNA sequencing of the epidermis and dorsal root ganglion in mouse models of diabetes.

Using these approaches, they found that the density of Langerhans cells was increased in male mice in parallel with mechanical allodynia, a type of neuropathic pain caused by light touch or stimuli.

In skin biopsies from patients with diabetic neuropathy, Langerhans cells exhibited increased volume and dendritic complexity, which correlated with diabetes duration.

Next, the investigators genetically depleted Langerhans cells in the mouse models. Unexpectedly, they discovered that depleting Langerhans cells prevented mechanical allodynia and spontaneous pain-like behavior in male mice but not in female mice. Subsequent single-cell and interactome analysis also revealed male-specific inflammatory Langerhans cell programming, including the upregulation of chemokine signaling pathways.

The findings identify epidermal Langerhans cells as drivers of pain in diabetic neuropathy, underscoring their potential as future therapeutic targets, according to Menichella. The study also underscores sex-dependent immune programs and cellular communication at the skin-nerve interface, which can help tailor future treatments for male versus female patients.

“Our study shows that there’s a communication problem in cells within the skin and nerves, and when that communication is not happening correctly, it causes pain and the degeneration of the nerves,” Menichella said. “Perhaps topical therapeutics could be effective and better tolerated by patients because most therapies for neuropathic pain systemically have many side effects, poorly tolerated by our patients suffering from diabetic neuropathy.”

Paola Pacifico, PhD, a postdoctoral fellow in the Menichella laboratory, was the lead author of the study.

Co-authors of the study include Abdelhak Belmadani, PhD, research associate professor of Pharmacology; Amy Paller, MD, MS, ‘81, ‘83 GME, chair and the Walter J. Hamlin Professor of Dermatology; and Richard Miller, PhD, Professor Emeritus of Pharmacology.

This research was partially supported by the Northwestern University Core Centers, the Italian Ministry of Health (RRC), and National Institutes of Health grants R01 NS104295-01, R01 AR077691-01 and R01 NS104295-01.