Conjunctival Goblet Cell Secretion Stimulated by Leukotrienes Is Reduced by Resolvins D1 and E1 To Promote Resolution of Inflammation

Abstract

The conjunctiva is a mucous membrane that covers the sclera and lines the inside of the eyelids. Throughout the conjunctiva are goblet cells that secrete mucins to protect the eye. Chronic inflammatory diseases such as allergic conjunctivitis and early dry eye lead to increased goblet cell mucin secretion into tears and ocular surface disease. The purpose of this study was to determine the actions of the inflammatory mediators, the leukotrienes and the proresolution resolvins, on secretion from cultured rat and human conjunctival goblet cells. We found that both cysteinyl leukotriene (CysLT) receptors, CysLT1 and CysLT2, were present in rat conjunctiva and in rat and human cultured conjunctival goblet cells. All leukotrienes LTB4, LTC4, LTD4, and LTE4, as well as PGD2, stimulated goblet cell secretion in rat goblet cells. LTD4 and LTE4 increased the intracellular Ca2+ concentration ([Ca2+]i), and LTD4 activated ERK1/2. The CysLT1 receptor antagonist MK571 significantly decreased LTD4-stimulated rat goblet cell secretion and the increase in [Ca2+]i. Resolvins D1 (RvD1) and E1 (RvE1) completely reduced LTD4-stimulated goblet cell secretion in cultured rat goblet cells. LTD4-induced secretion from human goblet cells was blocked by RvD1. RvD1 and RvE1 prevented LTD4- and LTE4-stimulated increases in [Ca2+]i, as well as LTD4 activation of ERK1/2. We conclude that cysteinyl leukotrienes stimulate conjunctival goblet cell mucous secretion with LTD4 using the CysLT1 receptor. Stimulated secretion is terminated by preventing the increase in [Ca2+]i and activation of ERK1/2 by RvD1 and RvE1.

ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands

“…As mentioned above, resolvins block inflammation and promote tissue repair in several in vivo and in vitro models (6,26,30), indicating potential therapeutic applications within the oral cavity. Our results indicate that ALX/FPR2 is expressed in human salivary glands with and without SS (Fig.…”

Leukotriene E 4 elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

“…Although we do find GPR99 expressed in both nasal and lung EpCs, a function for GPR99 in other cell types cannot be excluded. There are no reports of GPR99 function in human airways; however, LTE 4 elicits mucin release from both human conjunctival GCs (32) and human airway EpCs (33). Notably, asthmatic patients are more sensitive to LTE 4 -elicited airflow obstruction than healthy controls, a hyperresponsiveness not seen with either LTC 4 or LTD 4 (20)(21)(22)34).…”

Lipid Mediators in the Resolution of Inflammation

“…Recently, with conjunctiva goblet cells, both RvD1 and RvE1 reduced LTD 4 -and histamine-stimulated conjunctival goblet cell secretion (Dartt et al 2011;Li et al 2013). RvE1 delivered as its methyl ester in a murine model of dry eye improves the outcome measures of corneal staining and goblet cell density, indicating the potential of resolvins in the treatment of dry eye (de Paiva et al 2012).…”