Nociceptor neurons direct fibroblasts via a PACAP-VIPR2 axis to drive IL-11 production and colon healing

Mucosal healing remains a pivotal therapeutic endpoint in ulcerative colitis (UC) management, yet cellular mechanisms driving tissue repair remain elusive. Here we demonstrate that Pirt+ nociceptor endings dynamically grow into the granulation tissue during colonic mucosal restitution, releasing pituitary adenylate cyclase-activating polypeptide (PACAP) to orchestrate reparative processes. Absence of PACAP signaling in Pirt+ sensory neurons resulted in delayed healing, while exogenous PACAP administration accelerated mucosal restitution in experimental colitis models. Mechanistically, PACAP exerts its pro-reparative effects through vasoactive intestinal peptide receptor 2 (VIPR2), with pituitary adenylate cyclase-activating polypeptide receptor type 1 and vasoactive intestinal peptide receptor 1 playing negligible roles in this context. Mouse and human fibroblast expressed VIPR2. VIPR2+ fibroblasts increased during mucosal healing and accumulated in granulation tissue. Conditional deletion of VIPR2 in fibroblasts abolished PACAP-mediated tissue repair. The effects of PACAP on mucosal healing are mediated via interleukin-11 released by VIPR2+ fibroblast. Our findings demonstrate a neuron-fibroblast axis that orchestrates mucosal healing, highlighting its therapeutic potential as a novel target for UC management.