The Role of Neuropeptides in Pathogenesis of Dry Dye

Abstract

Neuropeptides are known as important mediators between the nervous and immune systems. Recently, the role of the corneal nerve in the pathogenesis of various ocular surface diseases, including dry eye disease, has been highlighted. Neuropeptides are thought to be important factors in the pathogenesis of dry eye disease, as suggested by the well-known role between the nervous and immune systems, and several recently published studies have elucidated the previously unknown pathogenic mechanisms involved in the role of the neuropeptides secreted from the corneal nerves in dry eye disease. Here, we reviewed the emerging concept of neurogenic inflammation as one of the pathogenic mechanisms of dry eye disease, the recent results of related studies, and the direction of future research.

Keywords: calcitonin gene-related peptide; corneal nerve; dry eye; neurogenic inflammation; neuropeptide; neuropeptide Y; pathogenesis; substance P; vasoactive intestinal peptide.

Figure 1

Schematic drawing for innervation of the lacrimal functional unit ALG: accessory lacrimal glands, CG: ciliary ganglion, CN: cranial nerve, FN: frontal nerve, GG: geniculate ganglion, ICA: internal carotid artery, LCN: long ciliary nerve, LG: lacrimal gland, LN: lacrimal nerve, MG: Meibomian gland, NN: nasociliary nerve, SCG: superior cervical ganglion, SCN: short ciliary nerve, SSN: superior salivatory nucleus, PPG: pterygopalatine (sphenopalatine) ganglion, TG: trigeminal ganglion (modified from Netter, FH, The Ciba Collection of Medical Illustrations, CIBA-Geigy Corporation, 1991).

Figure 2

NK1R blockade ameliorates pathological corneal lymphangiogenesis and improves clinical signs of dry eye in vivo. (a) Representative immunofluorescence images of whole-mount cornea stained with CD31 (red) and LYVE-1 (green) and quantification of the percentage of lymphatics area covered with LYVE-1 in the cornea tissue at 14 days after induction of dry eye in CEC. NK1R antagonist (L733,060, 6.6 µg/5 µL) for the DED treatment group or same volume of PBS for PBS group was administered through subconjunctival injection every 48 h to 72 h from day 0 to day 14 of DED induction by CEC. Each value represents the mean ± SEM of nine independent whole-mount cornea. * p < 0.05 by Mann-Whitney U test. Scale bar = 500 μm. (b) Representative corneal fluorescein staining images showing punctate epithelial erosion at 14 days after induction of dry eye in CEC. Quantification of corneal fluorescein staining scoring according to the standard National Eye Institute grading system (Bethesda, MD) and the amount of tears measured by the phenol red thread test. * p < 0.05, ** p < 0.01 by Mann-Whitney U test. n = 6. CEC: controlled environmental chamber, LYVE-1: lymphatic vessel endothelial hyaluronan receptor 1, NK1R: neurokinin-1 receptor, PBS: phosphate-buffered saline [221].