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

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ABSTRACT Piezo2 is a 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, we discovered that the Cx3cr1 Cre locus targets not only macrophages, but also a distinct subset of nerves. Spatial-RNAseq resolved that Cx3cr1 Cre -driven labeling was uniquely enriched in Piezo2-expressing neurons, a result of temporal Cx3cr1 expression during development. Through lineage tracing, scRNAseq, and imaging, we identified a novel tripartite cellular niche at the epithelial basement membrane, comprised of monocyte-derived macrophages, nerves, and Schwann cells. Additional scRNAseq and genetic studies revealed that Schwann cell-derived IL34 maintained corneal macrophages. Through pharmacologic and genetic perturbations, we also demonstrate corneal macrophages selectively maintained the structure-function of Piezo2-enriched nerve endings, with disruption of this niche causing specific deficits in mechanosensation while preserving other sensory modalities. Altogether, we describe a novel tricellular niche in the cornea required for Piezo2-mediated touch sensation, suggesting new directions for investigating mechanosensory circuits including proprioception.

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