Piezo1-Dependent Neuro-Immune Signaling in Macrophages Drives Colitis-Associated Visceral Pain [scRNA-Seq]

While neuro-immune interactions have been implicated in somatic pain, the contribution of specific immune cell subsets to colitis-associated visceral hypersensitivity is unclear. Here, we identify the mechanosensitive ion channel Piezo1 in CX3CR1+ resident macrophages as a key regulator of visceral pain in a murine model of dextran sulfate sodium (DSS)-induced colitis.

Single-cell RNA sequencing and functional assays revealed that Piezo1 is upregulated and functionally active in both resident and infiltrating macrophages during colitis. However, conditional deletion of Piezo1 in CX3CR1+ resident macrophages, but not in CCR2+ infiltrating macrophages, markedly attenuated visceral hypersensitivity and alleviated colonic inflammation. Mechanistically, Piezo1 activation induced NGF expression in resident macrophages, which engaged TrkA signaling to promote sensory nerve remodeling and visceral pain.