Advertisement

ResearchIn-Press PreviewDermatologyImmunologyNeuroscience Open Access | 10.1172/JCI192328

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

Paola Pacifico,1 Dale George,2 Nirupa D. Jayaraj,1 Dongjun Ren,3 James S. Coy-Dibley,1 Abdelhak A. Belmadani,3 Sofia Veronesi,1 Mirna Andelic,4 Daniele Cartelli,4 Grazia Devigili,4 Raffaella Lombardi,4 Giuseppe Lauria Pinter,4 Amy S. Paller,5 Richard J. Miller,3 and Daniela M. Menichella1

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Pacifico, P. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by George, D. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Jayaraj, N. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Ren, D. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Coy-Dibley, J. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Belmadani, A. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Veronesi, S. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Andelic, M. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Cartelli, D. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Devigili, G. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Lombardi, R. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Lauria Pinter, G. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Paller, A. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Miller, R. in: PubMed | Google Scholar

1Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2SonoThera, Inc., South San Francisco, United States of America

3Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

4Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

5Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

Find articles by Menichella, D. in: PubMed | Google Scholar

Published April 30, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI192328.
Copyright © 2026, Pacifico et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 30, 2026 - Version history
View PDF
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 non-neuronal 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 sequencing of epidermis and DRG, we found that LC density increased in male diabetic mice in parallel with mechanical allodynia. In human PDN skin, 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.

Supplemental material

View

Version history
  • Version 1 (April 30, 2026): In-Press Preview
Advertisement
Advertisement