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

Year: 2026

Type: preprint

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 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.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.11.06.764960

Institutions: Beth Israel Deaconess Medical Center, Harvard University, Wyss Institute for Biologically Inspired Engineering

Language: English

Topic: Wound Healing and Treatments

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

Open Access status: green

OpenAlex ID: W7225658589