Cholinergic modulation engages a CHRM1-IL-17 neuroimmune axis to promote diabetic wound repair

Li, Z.; Theocharidis, G.; Lee, S.; Kalavros, N.; Nagalakshmi, S. U.; Contreras, M.; Valsami, E.-A.; Nam, H.; Guan, M.; Chu, G.; Mezghani, I.; Wang, E.; Sumpio, B. J.; Hou, J.; Gennari-Felipe, M.; Gilman, J.; Lafuente-Gomez, N.; Maeso Aragon, L.; Dimitrakakis, N.; Arruda de Amaral, A.; Wang, S.; Vlachos, I. S.; Mooney, D. J.; Veves, A.

doi:10.64898/2026.11.06.764960

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bioRxiv · 10.64898/2026.11.06.764960

Cholinergic modulation engages a CHRM1-IL-17 neuroimmune axis to promote diabetic wound repair

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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.

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Li, Z., Theocharidis, G., Lee, S., Kalavros, N., Nagalakshmi, S. U., Contreras, M., Valsami, E.-A., Nam, H., Guan, M., Chu, G., Mezghani, I., Wang, E., Sumpio, B. J., Hou, J., Gennari-Felipe, M., Gilman, J., Lafuente-Gomez, N., Maeso Aragon, L., Dimitrakakis, N., Arruda de Amaral, A., Wang, S., Vlachos, I. S., Mooney, D. J., Veves, A.. 2026-11-09. Cholinergic modulation engages a CHRM1-IL-17 neuroimmune axis to promote diabetic wound repair. https://doi.org/10.64898/2026.11.06.764960

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