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bioRxiv · 10.64898/2026.06.15.732199

Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis

Zeng, Y.·Zhang, P.·Wu, F.·Tu, R.·Zhi, X.·Kobayashi, H.·Qian, J.·Ochiai, Y.·Zheng, B.·Zheng, H.·Li, S.·Lin, J.·Hata, M.·Waterbury, Q. T.·Arai, J.·Zamechek, L. B.·Wang, T. C.
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Abstract

Inflammatory memory has emerged as a fundamental principle by which prior injury shapes future tissue responses, yet whether sensory neurons participate in long-term tissue memory remains unknown. Here, we show that vagal sensory neurons acquire a durable, experience-dependent state following gastric injury or Helicobacter pylori infection, leading to enhanced regeneration, metaplasia, and tumor progression upon re-injury. This neuronal program is stable, functionally transferable, and sufficient to drive epithelial responses in vivo. Mechanistically, injury-activated ILC2s establish sensory neuronal memory through IL-13-dependent epigenetic remodeling, inducing SMYD4-mediated H3K4 trimethylation and promoting CGRP-dependent activation of gastric epithelial cells. Together, our findings support a model in which tissue memory is not restricted to epithelial or immune compartments but emerges through coordinated long-term adaptations across multiple cellular systems. Within this framework, sensory neurons provide a persistent substrate for recall responses, linking prior inflammatory experience to sustained epithelial plasticity and cancer susceptibility. HIGHLIGHTSO_LISensory neurons function as a durable compartment of tissue memory. C_LIO_LICGRP-RAMP1 signaling couples neuronal memory to gastric stem cells. C_LIO_LIILC2-derived IL-13 establishes sensory neuronal memory programs. C_LIO_LISMYD4-mediated H3K4me3 stabilizes long-term neuronal memory. C_LIO_LINeuronal memory promotes gastric regeneration and tumor susceptibility. C_LI

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Zeng, Y., Zhang, P., Wu, F., Tu, R., Zhi, X., Kobayashi, H., Qian, J., Ochiai, Y., Zheng, B., Zheng, H., Li, S., Lin, J., Hata, M., Waterbury, Q. T., Arai, J., Zamechek, L. B., Wang, T. C.. 2026-06-19. Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis. https://doi.org/10.64898/2026.06.15.732199

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