An autonomous macrophage-nociceptor mechanosensory relay drives chronic visceral pain.

Previously, a molecular framework already existed for how mechanical stimuli enter pain pathways: Piezo1 and Piezo2 are considered components of distinct mechanically activated cation channels, with Piezo2 playing an essential role in the decay of rapidly adapting mechanocurrents in dorsal root ganglion neurons ^[2]; persistent injury can in turn induce plasticity in peripheral and central pain transmission pathways, intensifying pain and giving rise to hyperalgesia ^[1]. In ulcerative colitis–associated visceral pain, however, the inflammatory cascade has long been regarded as the principal explanation, and whether immune cells can directly convert mechanical cues into nociceptive signals has remained unclear.

Single-cell studies have shown that the greatest differences among patients with inflammatory bowel disease are concentrated in the myeloid cell compartment, and spatial analyses have further resolved macrophage subpopulations and their communication networks with fibroblasts ^[3]. Other work has shown that resident macrophages in the lamina propria outside the muscularis can prune synapses, phagocytose enteric neurons, and participate in maintaining the enteric nervous system ^[4]; that work, however, focused on the development and maintenance of the enteric nervous system rather than nociception. This study pushes the question to a more direct causal level: does Piezo1 in tissue-resident CX3CR1+ macrophages directly convert mechanical stimuli into neural sensitization signals?

The study's answer is affirmative. Piezo1 triggers Ca2+ influx and NF-κB nuclear translocation; the latter occupies the Ngf promoter and induces synthesis of nerve growth factor (NGF). Macrophage-derived NGF then remodels and sensitizes the peripheral terminals of TRPV1+ nociceptive afferents within the neuroimmune unit, forming a continuous chain of “mechanical force—Piezo1—NGF—TrkA—sensory nerve.” In a mildly inflamed intracolonic zymosan model, the Piezo1–NGF–TrkA axis acts as a direct mechanosensory relay that is largely independent of the cytokine cascade.

The causal evidence comes from three types of genetic deletions: deletion of Piezo1 or Ngf in resident macrophages, and deletion of Ntrk1 in TRPV1+ neurons, all of which abolished visceral hyperalgesia in both inflammatory and non-inflammatory models. Relative to existing understanding, this study advances resident immune cells from participants in inflammatory responses to mechanosensors and neuromodulators, and establishes a parallel pain pathway that reaches directly to sensory nerves. What remains to be answered are the boundaries of applicability of this axis across different colonic mechanical environments and different visceral pain disorders, as well as the clinical feasibility and safety of targeting this axis; the current results do not yet address these questions.