Cholinergic modulation engages a CHRM1-IL-17 neuroimmune axis to promote diabetic wound repair
- 1Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical S
Abstract
Chronic non-healing wounds are a major complication of diabetes, where persistent inflammation fails to transition into effective tissue repair (1-3). Here we identify cholinergic modulation as a mechanism that promotes productive inflammation and diabetic wound healing. Using a healing-associated fibroblast signature derived from single-cell profiling of human diabetic foot ulcers (3), we identified the acetylcholinesterase (AChE) inhibitor metrifonate as a candidate inducer of reparative wound programs. Topical delivery accelerated healing in diabetic mice and increased acetylcholine availability within the wound. Complementary receptor pharmacology identified muscarinic acetylcholine receptor 1 (CHRM1) as the principal receptor mediating the reparative response. Transcriptomic and cellular analyses revealed early induction of IL-17-associated inflammatory programs and enrichment of CHRM1NK1.1 innate lymphocytes. Depletion of NK1.1 cells or neutralization of IL-17A abolished the pro-healing effect, whereas spatial transcriptomics revealed treatment-associated organization of NK cells within vascular niches. Localized treatment further promoted repair in diabetic porcine wounds and human skin models. Together, these findings identify a CHRM1-IL-17 neuroimmune axis linking cholinergic modulation to diabetic wound repair and establish local AChE inhibition as a potential therapeutic strategy for chronic wounds.
Related
- Cholinergic and adrenergic modulation sculpts parallel inhibition of SST-INs in visual cortex
- Myricitrin Delays Caenorhabditis elegans Aging: Association with DAF-16, SIR-2.1, and Potential Cholinergic Modulation.
- Cholinergic Modulation of Proteinoid Microsphere Networks as Prebiotic Depression Models
- Citrate-Based Hydrogels Promote Closure of Infected Diabetic Wounds
- Identification of the miR-210-3p-EFNA3-YAP axis and its targeted modulation via biomimetic supramolecular nanoparticles to promote ischemic flap survival.
BibTeX
@misc{li2026cholinergic,
title = {{Cholinergic modulation engages a CHRM1-IL-17 neuroimmune axis to promote diabetic wound repair}},
author = {Z. Li and G. Theocharidis and S. Lee and N. Kalavros and S. U. Nagalakshmi and M. Contreras and E.-A. Valsami and H. Nam and M. Guan and G. Chu and I. Mezghani and E. Wang and B. J. Sumpio and J. Hou and M. Gennari-Felipe and J. Gilman and N. Lafuente-Gomez and L. Maeso Aragon and N. Dimitrakakis and A. Arruda de Amaral and S. Wang and I. S. Vlachos and D. J. Mooney and A. Veves},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764960},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764960v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cholinergic modulation engages a CHRM1-IL-17 neuroimmune axis to promote diabetic wound repair
AU - Z. Li
AU - G. Theocharidis
AU - S. Lee
AU - N. Kalavros
AU - S. U. Nagalakshmi
AU - M. Contreras
AU - E.-A. Valsami
AU - H. Nam
AU - M. Guan
AU - G. Chu
AU - I. Mezghani
AU - E. Wang
AU - B. J. Sumpio
AU - J. Hou
AU - M. Gennari-Felipe
AU - J. Gilman
AU - N. Lafuente-Gomez
AU - L. Maeso Aragon
AU - N. Dimitrakakis
AU - A. Arruda de Amaral
AU - S. Wang
AU - I. S. Vlachos
AU - D. J. Mooney
AU - A. Veves
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764960
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764960v1
AB - Chronic non-healing wounds are a major complication of diabetes, where persistent inflammation fails to transition into effective tissue repair (1-3). Here we identify cholinergic modulation as a mechanism that promotes productive inflammation and diabetic wound healing. Using a healing-associated fibroblast signature derived from single-cell profiling of human diabetic foot ulcers (3), we identified the acetylcholinesterase (AChE) inhibitor metrifonate as a candidate inducer of reparative wound programs. Topical delivery accelerated healing in diabetic mice and increased acetylcholine availability within the wound. Complementary receptor pharmacology identified muscarinic acetylcholine receptor 1 (CHRM1) as the principal receptor mediating the reparative response. Transcriptomic and cellular analyses revealed early induction of IL-17-associated inflammatory programs and enrichment of CHRM1NK1.1 innate lymphocytes. Depletion of NK1.1 cells or neutralization of IL-17A abolished the pro-healing effect, whereas spatial transcriptomics revealed treatment-associated organization of NK cells within vascular niches. Localized treatment further promoted repair in diabetic porcine wounds and human skin models. Together, these findings identify a CHRM1-IL-17 neuroimmune axis linking cholinergic modulation to diabetic wound repair and establish local AChE inhibition as a potential therapeutic strategy for chronic wounds.
ER -