Lipoxin A4 Counter-regulates Histamine-stimulated Glycoconjugate Secretion in Conjunctival Goblet Cells.

Robin R Hodges,Charles N Serhan,Darlene A Dartt,Dayu Li,Marie A Shatos

doi:10.1038/srep36124

Abstract

Conjunctival goblet cells synthesize and secrete mucins which play an important role in protecting the ocular surface. Pro-resolution mediators, such as lipoxin A4 (LXA4), are produced during inflammation returning the tissue to homeostasis and are also produced in non-inflamed tissues. The purpose of this study was to determine the actions of LXA4 on cultured human conjunctival goblet cell mucin secretion and increase in intracellular [Ca2+] ([Ca2+]i) and on histamine-stimulated responses. LXA4 increased mucin secretion and [Ca2+]i, and activated ERK1/2 in human goblet cells. Addition of LXA4 before resolvin D1 (RvD1) decreased RvD1 responses though RvD1 did not block LXA4 responses. LXA4 inhibited histamine-stimulated increases in mucin secretion, [Ca2+]i, and ERK1/2 activation through activation of β-adrenergic receptor kinase 1. We conclude that conjunctival goblet cells respond to LXA4 through the ALX/FPR2 receptor to maintain homeostasis of the ocular surface and regulate histamine responses and could provide a new therapeutic approach for allergic conjunctivitis and dry eye diseases.

Highlights

Conjunctival goblet cells are specialized cells that span the thickness of the conjunctiva from the ocular surface to the stroma
We investigated the actions of lipoxin A4 (LXA4) with cultured human conjunctival goblet cells, as well as the impact of LXA4 on histamine-stimulated increase in [Ca2+]i, mucin secretion, and extracellular regulated kinase (ERK) 1/2 activation in rat and human goblet cells
In addition to ALX/FPR2, resolvin D1 (RvD1) and LXA4 bind to the receptor GPR3226, which we previously demonstrated to be present in cultured human goblet cells[20]

Summary

Introduction

Conjunctival goblet cells are specialized cells that span the thickness of the conjunctiva from the ocular surface to the stroma These cells synthesize and secrete mucins which include the gel forming mucin MUC5AC in humans and in rats[1,2]. We previously showed that goblet cells of the conjunctiva play an active role in the response of the ocular surface to histamine and leukotriene challenge[15,16,17]. Termination of inflammation occurs with the biosynthesis of the specialized pro-resolution mediators (SPMs) resolvins (Rvs), lipoxins (LX), maresins, and protectins from omega-3 and -6 essential fatty acids[18] These resolution-phase mediators alter the magnitude and the duration of the inflammatory response through mechanisms involving counter regulation of inflammatory mediators as well as phagocytosis of microbes and cell www.nature.com/scientificreports/. RvD1 and its epimer aspirin-triggered RvD1 (AT-RvD1), and RvE1 appear to have two functions (1) alone these compounds increase [Ca2+]i, activate extracellular regulated kinase (ERK) 1/2, and stimulate mucin secretion and (2) block LTD4- and histamine-stimulated increase in [Ca2+]i and mucin secretion[19,20]

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