CX3CR1+ Macrophages Drive Persistent Visceral Pain via Piezo1-NGF Axis in Colitis Models

Researchers induced colitis with 2.5% DSS in drinking water for seven days and used rectal zymosan to produce stiffness without active inflammation. They recorded abdominal EMG responses to graded colorectal balloon distension from 20 to 80 µl. Selective deletion of Piezo1 or Ngf in CX3CR1+ cells, or Ntrk1 in Trpv1 neurons, abolished mechanical hypersensitivity in both inflammatory and post-inflammatory phases. Calcium influx through Piezo1 activated NF-κB binding to the NGF promoter, providing a mechanical-to-neurotrophic link independent of cytokine release.

Current cytokine-centric models of IBD pain do not explain why anti-inflammatory therapy often fails to relieve symptoms once ulcers heal. The identified pathway supplies a plausible mechanism: residual tissue stiffness after mucosal healing continues to engage resident macrophages. This reframes post-inflammatory visceral hypersensitivity as a mechanosensory rather than purely inflammatory process and suggests why existing analgesics remain inadequate.

The work builds on prior observations that Piezo1 mediates macrophage responses to substrate rigidity in other tissues and that NGF-TrkA signaling heightens nociceptor excitability. It also aligns with clinical reports of elevated NGF in mucosal biopsies from patients with quiescent IBD yet ongoing pain. Whether the same axis operates in human colonic macrophages remains untested.

Next steps include development of macrophage-targeted Piezo1 antagonists or NGF-neutralizing antibodies and correlation of colonic stiffness measured by endoscopic elastography with patient-reported pain scores in longitudinal cohorts.