Lacritin acutely enhances corneal nerve sensitivity to ocular surface dryness as a key stimulus for basal tear production: Implications for dry eye disease.

摘要

Purpose : Lacritin is one of relatively few tear proteins selectively down-regulated in dry eye. Topical lacritin heals wounded corneas, and in dry eye animals restores both tear production and ocular surface homeostasis. The ion channel TRPM8 on corneal sensory nerves detects corneal drying to thereby stimulate basal tearing. Here we asked whether topical lacritin influences the drying sensitivity of TRPM8 rat corneal sensory nerves, and probed the mechanism of lacritin cell targeting. Methods : Extracellular recordings were made from single trigeminal ganglion neurons innervating the cornea of normal rats. Neurons were selected for those responding to a slight cooling (1oC) and drying of the ocular surface, and thus likely express TRPM8. Their responses to corneal dryness (dry responses) were recorded before and 1 hr after ocular instillation of recombinant human lacritin, or its inactive truncation control, C-25. Since lacritin targets cells in part via heparanase-modified cell surface syndecan-1, experiments were also performed following pre-treatment with single chain anti-3-O-sulfated heparan sulfate antibody HS4C3, or with its negative control MPB49. Results : One-hour ocular instillation of lacritin, but not C-25, significantly increased the dry response by ~25% from the pre-lacritin value. The enhanced responses returned to the control level after washing the cornea with artificial tears. Inhibiting lacritin binding to co-receptor, syndecan-1, with HS4C3 appeared to abrogate the lacritin increase. Conclusions : Lacritin appears to act as a stimulatory signal to enhance the activity of the corneal nerves. It is thereby capable of boosting basal tear production via as-yet unknown local mechanisms. The first stage of its action appears to involve lacritin to syndecan-1 binding on the ocular surface. By stimulating the lacrimal functional unit, lacritin can be used as a potential biotherapeutic to treat dry eye disease. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.