Ocular TRPV1 deficiency protects from dry eye-induced corneal nerve damage

Abstract

AbstractBackgroundCorneal nerve damage causes the most clinically significant symptoms in dry eye disease (DED) yet its pathophysiology remains poorly understood. Transient receptor potential vanilloid-1 (TRPV1) channels abound in corneal nerve fibers and respond to inflammation-derived ligands, which increase in DED. TRPV1 overactivation promotes axonal degeneration in vitro but whether it contributes to corneal neuropathy is unknown. Therefore, here we explored the role of TRPV1 in DED-associated corneal nerve damage.MethodsSurgical DED was induced in TRPV1-deficient (TRPV1KO) and wild-type (wt) mice. Corneal nerve function was measured on days 0, 5, and 10 by mechanical and capsaicin sensitivity and eye-closing ratio as an indicator of non-evoked pain. Nerve and epithelial morphology was evaluated by confocal microscopy of corneal wholemounts. Pharmacological TRPV1 inhibition in wild-type mice was also evaluated.Resultswt and TRPV1KO mice developed comparable ocular desiccation and corneal epithelial damage. Contrasting with wt mice, corneal mechanosensitivity in TRPV1KO mice did not decrease with disease progression. Capsaicin sensitivity increased in wt mice with DED, and consistently, wt but not TRPV1KO mice with DED displayed signs of non-evoked pain. Wt mice with DED exhibited nerve degeneration throughout the corneal epithelium whereas TRPV1KO mice only developed a reduction in the most superficial nerve endings that failed to propagate to the deeper subbasal corneal nerves. Pharmacological blockade of ocular TRPV1 activity reproduced these findings in wt mice with DED. Although TRPV1KO mice with DED had fewer pathogenic Th1 and Th17 CD4+ T cells in the lymph nodes, conjunctival immune infiltration was comparable between strains. Moreover, CD4+ T cells from wt and TRPV1KO mice with DED were equally pathogenic when transferred into T cell-deficient mice, confirming that TRPV1 activity in T cells is not involved in corneal neuropathy.ConclusionsAlthough ocular desiccation is sufficient to trigger superficial corneal nerve damage in DED, proximal propagation of axonal degeneration requires TRPV1 signaling. Conversely, local inflammation sensitizes ocular TRPV1 channels, which are also involved in ocular pain, a key symptom of the disease. Thus, our findings suggest that ocular TRPV1 overactivation is a driving force in DED-associated corneal neuropathy and a potential therapeutic target.Graphical abstract