Transient receptor potential vanilloid 1-deficiency protects from immune-mediated corneal nerve damage in dry eye

Abstract

Purpose : Transient receptor potential vanilloid 1 (TRPV1) channels are known to be involved in neurogenic inflammation and neurodegeneration in non-ocular tissues. TRPV1 channels are activated by inflammatory stimuli and we have reported increased TRPV1 signaling in dry eye. Here we hypothesized that TRPV1 channels could play a role in dry eye-associated corneal nerve damage.

Methods : Dry eye was induced for 10 days in 6-8-week-old C57BL/6 (wt) and TRPV1KO mice of both sexes by bilateral excision of the extraocular lacrimal glands. Conventional dry eye parameters were assessed along with corneal nerve function (mechanical sensitivity) and morphology (βIII tubulin staining). Also, CD4+ T cells from both strains were adoptively transferred to RAG1KO recipient mice and pharmacological inhibition of TRPV1 signaling was tested in wt mice (ocular SB-366791 instillation).

Results : Wt and TRPV1KO mice with dry eye had comparable tear deficiency (17±7 vs 23±18%, p=0.4), corneal epithelial damage (mean fluorescence 11.8±0.8 vs 11.1±0.6, p=0.6) and conjunctival CD4+ T cell infiltration (7.8±1.4% vs 3.1±0.1%, p>0.05). Also, there was no difference in interferon gamma- (2.85±3.62 vs 1.73±2.2, p=0.4) and interleukin 17-producing (2.4±4.6 vs 1.9±5.1, p=0.9) CD4+ T cells in the draining lymph nodes. Regarding the corneal nerves, TRPV1KO mice had significantly higher corneal mechanical sensitivity than wt mice at baseline (4.6±0.09 vs 3.75±0.1 cm, p<0.05). Intriguingly, corneal sensitivity in TRPV1KO mice was not affected by dry eye (-4%, p=0.3), which contrasted the observed drop in wt mice (-21%, p<0.01). In line with this finding, there was a trend for less dry eye-induced change in corneal nerve morphology in TRPV1KO than in wt mice (-4±9% vs -11±9%, p>0.05). Finally, adoptive transfer of CD4+ T cells from wt and TRPV1KO mice with dry eye to mice with normal TRPV1 expression and no dry eye led to comparable loss in corneal mechanical sensitivity in both groups. TRPV1 inhibition reduced dry eye-associated corneal sensitivity loss in wt mice.

Conclusions : These findings suggest that dry eye-induced corneal neuropathy depends on TRPV1 signaling and that it is independent from corneal epitheliopathy because TRPV1KO mice did not differ in any of the non-neural aspects of the disease. Moreover, TRPV1 signaling in corneal epithelium/nerves seems to be more relevant than in pathogenic CD4+ T cells.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.