The Cornea Harbors a Tricellular Neuro-Immune Niche that Underpins Touch Sensation

Abstract

Piezo2 is a crucial mechanosensitive ion channel essential for touch and proprioception, yet the mechanisms that maintain this sensory modality in adult tissues are unknown. Using multiphoton imaging of the cornea in live mice, this work demonstrates that the Cx3cr1Cre locus labels not only macrophages, but also a distinct subset of nerves. Spatial-RNAseq resolved that Cx3cr1Cre nerve labeling was not stochastic but enriched within Piezo2-expressing neurons, likely a result of temporal Cx3cr1 expression during development. Through lineage tracing, scRNAseq, and imaging, this work identifies a novel tripartite cellular niche at the epithelial basement membrane, comprising corneal macrophages (monocyte-derived), nerves, and Schwann cells. Additional scRNAseq and knockout mouse studies revealed that IL-34 is expressed by Schwann cells and maintained corneal macrophages. Through pharmacologic and genetic perturbations, results demonstrate that corneal macrophages selectively maintained the structure and function of Piezo2-enriched nerve endings. Together, this work reveals a previously unrecognized tripartite cellular niche required for Piezo2-mediated touch sensation, suggesting new directions for investigating mechanosensory circuits including proprioception across tissues.