Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion

Abstract

Resolution of inflammation is an active process mediated by pro-resolution lipid mediators. Since resolvin (Rv) D1 is produced in the cornea, pro-resolution mediators could be effective in regulating inflammatory responses to histamine in allergic conjunctivitis. Two key mediators of resolution are the D-series resolvins RvD1 or aspirin-triggered RvD1 (AT-RvD1). We used cultured conjunctival goblet cells to determine whether histamine actions can be terminated during allergic responses. We found cross-talk between two types of G protein-coupled receptors, as RvD1 interacts with its receptor GPR32 to block histamine-stimulated H1 receptor increases in intracellular [Ca2+] ([Ca2+]i) preventing H1 receptor-mediated responses. In human and rat conjunctival goblet cells RvD1 and AT-RvD1 each block histamine-stimulated secretion by preventing its increase in [Ca2+]i and activation of extracellular regulated protein kinase (ERK)1/2. We suggest that D-series resolvins regulate histamine responses in the eye and offer new treatment approaches for allergic conjunctivitis or other histamine-dependent pathologies.

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

“…Resolvins have been shown to activate intracellular kinases, including Erk1/2 and Akt, which regulate cell survival and integrity (25,30,31,35). The results of the current study demonstrate that activation of ALX/FPR2 with AT-RvD1 also stimulates Erk1/2 and Akt phosphorylation in mSMG cells ( Fig.…”

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B 4 synthesis by inhibiting a calcium-activated kinase pathway

“…S6). In this regard, RvD1 was recently reported to block histamine-stimulated intracellular calcium in goblet cells in a receptor-dependent manner (32), and the SPM resolvin E1 was shown to block intracellular calcium initiated by the antimicrobial peptide LLGDFFRKSKE-KIGKEFKRIVQRIKDFLRNLVPRTES (LL-37) in PMNs (33). Interestingly, another study showed that LL-37 stimulated p38 and LTB 4 formation in PMNs (34), although the signal transduction pathway leading to p38 activation was not elucidated.…”

Conjunctival epithelial and goblet cell function in chronic inflammation and ocular allergic inflammation

“…Histamine itself and agonists of all four histamine receptors each stimulate goblet cell secretion and antagonists block histamine-stimulated goblet cell secretion [32]. Histamine induces mucin secretion by increasing the intracellular [Ca 2+ ] and activating extracellular regulated kinase (ERK1/2) [33, 34]. Thus goblet cells are a direct target of one of the important allergic mediators, histamine.…”