Skin-resident Langerhans cells drive neuropathic pain via chemokine-dependent neuron-immune communication.

Overview

1. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
2. SonoThera Inc., South San Francisco, California, USA
3. Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
4. Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
5. Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
6. Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

Abstract

Neuropathic pain affects over 20 million people in the United States, and painful diabetic neuropathy (PDN), a common complication of diabetes, is among its most prevalent and treatment-resistant forms. Although PDN is characterized by nociceptor dysfunction, the upstream peripheral mechanisms remain incompletely understood. While dorsal root ganglion (DRG) nociceptor hyperexcitability is a hallmark of PDN, emerging evidence suggests that nonneuronal skin cells may modulate nociceptor function. Here, we investigated whether epidermal Langerhans cells (LCs) contribute to neuropathic pain in PDN through neuroimmune signaling. Using a clinically relevant high-fat diet (HFD) mouse model, transgenic LC ablation, behavioral assays, human skin biopsies, and single-cell RNA seq of epidermis and DRG, we found that LC density increased in male diabetic mice in parallel with mechanical allodynia. In skin samples of people with PDN, LCs exhibited increased volume and dendritic complexity correlating with diabetes duration. Genetic depletion of LCs prevented mechanical allodynia and spontaneous pain-like behavior in male, but not female, HFD mice, revealing a sex-dependent contribution. Single-cell and interactome analyses identified male-specific inflammatory LC programs, including upregulation of chemokine signaling pathways. Consistently, LC secretome profiling showed increased CCL2 release, and local CCR2 blockade reversed allodynia. These findings identify epidermal LCs as peripheral regulators of PDN pain and highlight sex-dependent chemokine-mediated neuron-immune communication at the skin-nerve interface.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE327170, at NCBI GEO; found in “Data availability.”

Data availability

All data presented in this study are included in the main text and Supplemental figures. The scRNA-seq data generated from paw epidermis of male and female RD and HFD mice have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE327170 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE327170). All data underlying the graphs are provided in the Supporting Data Values file.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 6 keywords, 15 MeSH terms, 1 funder, 114 references.

Cite

This paper

Pacifico, P., George, D., Jayaraj, N. D., Ren, D., Coy-Dibley, J. S., Belmadani, A. A., Veronesi, S., Andelic, M., Cartelli, D., Devigili, G., Lombardi, R., Pinter, G. L., Paller, A. S., Miller, R. J., & Menichella, D. M. (2026). Skin-resident Langerhans cells drive neuropathic pain via chemokine-dependent neuron-immune communication. The Journal of clinical investigation, 136(12), e192328. https://doi.org/10.1172/jci192328

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