Abstract Corneal neurosensory abnormalities cause pain and discomfort in ocular surface disease, yet their pathophysiology is poorly understood. Here we show that in a mouse dry eye model, the ocular (over)activation of transient receptor potential vanilloid 1 (TRPV1) channels in response to tear deficiency and tissue damage promotes neuroinflammatory gene expression and macrophage reactivity in the trigeminal ganglion, where the cornea-innervating sensory neurons are located. This is accompanied by ocular surface macrophage activation, impaired corneal sensitivity to mechanical and non-TRPV1-mediated chemical stimulation, reduced corneal nerve density and the sensitization of ocular TRPV1 channels, thus establishing a vicious neurosensory cycle. Isolated corneal TRPV1 activation without ocular desiccation recapitulates macrophage reactivity, corneal nerve degeneration and trigeminal neuroinflammation, whereas the ocular substance P blockade reverts most of the TRPV1-driven corneal neurosensory abnormalities. Our study identifies a corneal–trigeminal axis that facilitates corneal neurosensory dysfunction and suggests potential targets for the treatment of ocular surface disease-associated corneal neuropathy.
Pizzano et al. (Wed,) studied this question.