Cholinergic modulation engages a CHRM1-IL-17 neuroimmune axis to promote diabetic wound repair
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 CHRM1⁺NK1.1⁺ 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.
Authors
- David J. Mooney (ORCID: https://orcid.org/0000-0001-6299-1194)
- Enya Wang (ORCID: https://orcid.org/0000-0002-5988-7780)
- Shuoshuo Wang (ORCID: https://orcid.org/0000-0002-5269-7044)
- Guangyu Chu (ORCID: https://orcid.org/0000-0002-1358-1698)
- Brandon J. Sumpio (ORCID: https://orcid.org/0000-0001-8372-3607)
- Eleftheria‐Angeliki Valsami (ORCID: https://orcid.org/0009-0007-4078-9084)
- Georgios Theocharidis (ORCID: https://orcid.org/0000-0002-8895-9130)
- Ioannis S. Vlachos (ORCID: https://orcid.org/0000-0002-8849-808X)
- Lidia Maeso (ORCID: https://orcid.org/0000-0001-9195-0412)
- Nuria Lafuente‐Gómez (ORCID: https://orcid.org/0000-0001-9269-3163)
- Ikram Mezghani (ORCID: https://orcid.org/0000-0001-6252-2670)
- Ming Guan (ORCID: https://orcid.org/0000-0001-5626-0790)
- Hyangsu Nam (ORCID: https://orcid.org/0000-0003-0990-077X)
- Matheus Gennari-Felipe (ORCID: https://orcid.org/0000-0001-6413-7952)
- Nikolaos Dimitrakakis
- Nikolaos Kalavros (ORCID: https://orcid.org/0000-0001-5503-9808)
- Zhuqing Li (ORCID: https://orcid.org/0009-0003-6568-7202)
- Antonella Arruda de amaral (ORCID: https://orcid.org/0009-0000-7704-5352)
- Mauricio Contreras (ORCID: https://orcid.org/0009-0002-9821-8536)
- Jessica Gilman
- Sheethal Umesh Nagalakshmi (ORCID: https://orcid.org/0009-0003-1187-0706)
- Aristidis Veves
- Jinfei Hou
- Sangmin Lee
Institutions
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Wyss Institute for Biologically Inspired Engineering (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-11-09
- DOI
- https://doi.org/10.64898/2026.11.06.764960
- Primary Topic
- Wound Healing and Treatments
- Type
- preprint