Distribution of Corneal TRPV1 and Its Association With Immune Cells During Homeostasis and Injury

Abstract

PURPOSE.Given the role of corneal sensory nerves during epithelial wound repair, we sought to examine the relationship between immune cells and polymodal nociceptors following corneal injury. METHODS.Young C57BL/6J mice received a 2 mm corneal epithelial injury. One week later, corneal wholemounts were immunostained using β-tubulin-488, TRPV1 (transient receptor potential ion channel subfamily V member-1, a nonselective cation channel) and immune cell (MHC-II, CD45 and CD68) antibodies. The sum length of TRPV1 + and TRPV1nerve fibers, and their spatial association with immune cells, was quantified in intact and injured corneas.RESULTS. TRPV1 + nerves account for ∼40% of the nerve fiber length in the intact corneal epithelium and ∼80% in the stroma. In the superficial epithelial layers, TRPV1 + nerve terminal length was similar in injured and intact corneas. In intact corneas, the density (sum length) of basal epithelial TRPV1 + and TRPV1 − nerve fibers was similar, however, in injured corneas, TRPV1 + nerve density was higher compared to TRPV1 − nerves. The degree of physical association between TRPV1 + nerves and intraepithelial CD45 + MHC-II + CD11c + cells was similar in intact and injured corneas. Stromal leukocytes coexpressed TRPV1, which was partially localized to CD68 + lysosomes, and this expression pattern was lower in injured corneas.CONCLUSIONS. TRPV1 + nerves accounted for a higher proportion of corneal nerves after injury, which may provide insights into the pathophysiology of neuropathic pain following corneal trauma. The close interactions of TRPV1 + nerves with intraepithelial immune cells and expression of TRPV1 by stromal macrophages provide evidence of neuroimmune interactions in the cornea.

Ocular nociception and neuropathic pain initiated by blue light stress in C57BL/6J mice

“…49 TRPV1 nerves were accounted for a higher proportion of corneal nerves at the ocular surface. 1,26 Despite its insensitivity to cold, TRPV1 has been shown to sensitize TRPM8 1 sensory neurons and promote neuropeptide substance P (SP) release to signal cold nociception. 29 TRPV4 is responsible for sensing hypoosmotic and mechanical signals.…”

Changes in TRPV1 Expression as Well as Substance P and Vasoactive Intestinal Peptide Levels Are Associated with Recurrence of Pterygium

“…TRPV1 is expressed in both neuronal and non-neuronal cells. It was shown that TRPV1+ nerves account for ~40% of nerve fiber length in the intact corneal epithelium and ~80% in the stroma and that following injury, TRPV1+ nerve density increases in a mouse model [ 28 ]. The activation of TRPV1+ nerves in the eye induces the release of neuropeptides such as neurokinins, calcitonin gene-related peptide (CGRP), and substance P (SP) [ 29 ].…”

Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics

“…Apart from inflammation enhancing the activity of existing receptors via phosphorylation, it also causes the de novo transcription of additional ion channels (Goldstein et al, 2019;Sachs et al, 2002;Tran et al, 2000).Altered signaling of many channels, including voltage-gated sodium (Nav1.7-1.9), potassium, and calcium channels, issues downstream effector pathways. In corneal neuropathic pain, ion channel expression and overproduction of TRP receptors, ASIC1 and ASIC3, occur in the trigeminal ganglion (Fakih et al, 2022;Jiao et al, 2021). Abnormalities in the processes of these ion channels are suggested to be heavily implicated in corneal neuropathic pain, warranting further study.…”