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. Sorted fibroblast from wild-type or Vipr2-KO mice were stimulated with PACAP(100nM) or vehicle (PBS, 0 nM PACAP) for 12 hour for RNA-seq.

黏膜愈合（mucosal healing）仍是溃疡性结肠炎（ulcerative colitis, UC）管理中的关键治疗终点，但其驱动组织修复的细胞机制仍不甚明晰。本研究证实，在结肠黏膜修复过程中，Pirt阳性伤害性神经末梢（Pirt+ nociceptor endings）会动态长入肉芽组织，释放垂体腺苷酸环化酶激活多肽（pituitary adenylate cyclase-activating polypeptide, PACAP）以调控修复进程。Pirt+感觉神经元中垂体腺苷酸环化酶激活多肽信号通路的缺失会延缓愈合，而外源性给予垂体腺苷酸环化酶激活多肽可加速实验性结肠炎模型中的黏膜修复。从机制上看，垂体腺苷酸环化酶激活多肽通过血管活性肠肽受体2（vasoactive intestinal peptide receptor 2, VIPR2）发挥促修复作用，而1型垂体腺苷酸环化酶激活多肽受体（pituitary adenylate cyclase-activating polypeptide receptor type 1）与血管活性肠肽受体1（vasoactive intestinal peptide receptor 1, VIPR1）在此过程中作用可忽略不计。小鼠与人类成纤维细胞均表达VIPR2。黏膜愈合过程中，VIPR2阳性（VIPR2+）成纤维细胞数量增多，并在肉芽组织中聚集。成纤维细胞中条件性敲除VIPR2可阻断垂体腺苷酸环化酶激活多肽介导的组织修复。垂体腺苷酸环化酶激活多肽对黏膜愈合的作用，由VIPR2+成纤维细胞释放的白细胞介素-11所介导。本研究揭示了一条调控黏膜愈合的神经元-成纤维细胞信号轴，凸显其作为溃疡性结肠炎管理新靶点的治疗潜力。本研究将野生型或Vipr2基因敲除（Vipr2-KO）小鼠的分选成纤维细胞用100nM垂体腺苷酸环化酶激活多肽或对照溶剂（磷酸盐缓冲液，phosphate buffered saline, PBS，0nM PACAP）刺激12小时，随后进行RNA测序（RNA-seq）。