Purpose of review Although conjunctival goblet cells are a major cell type in ocular mucosa, their responses during ocular allergy are largely unexplored. This review summarizes the recent findings that provide key insights into the mechanisms by which their function and survival are altered during chronic inflammatory responses, including ocular allergy. Recent findings Conjunctiva represents a major component of the ocular mucosa that harbors specialized lymphoid tissue. Exposure of mucin-secreting goblet cells to allergic and inflammatory mediators released by the local innate and adaptive immune cells modulates proliferation, secretory function, and cell survival. Allergic mediators like histamine, leukotrienes, and prostaglandins directly stimulate goblet cell mucin secretion and consistently increase goblet cell proliferation. Goblet cell mucin secretion is also detectable in a murine model of allergic conjunctivitis. Additionally, primary goblet cell cultures allow evaluation of various inflammatory cytokines with respect to changes in goblet cell mucin secretion, proliferation, and apoptosis. These findings in combination with the preclinical mouse models help understand the goblet cell responses and their modulation during chronic inflammatory diseases, including ocular allergy. Summary Recent findings related to conjunctival goblet cells provide the basis for novel therapeutic approaches, involving modulation of goblet cell mucin production, to improve treatment of ocular allergies.

Resolution of inflammation is an active process mediated by pro-resolution lipid mediators. As 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 (GPRs), 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.

Goblet cells populate wet-surfaced mucosa including the conjunctiva of the eye, intestine, and nose, among others. These cells function as part of the innate immune system by secreting high molecular weight mucins that interact with environmental constituents including pathogens, allergens, and particulate pollutants. Herein, we determined whether interferon gamma (IFN-γ), a Th1 cytokine increased in dry eye, alters goblet cell function. Goblet cells from rat and human conjunctiva were cultured. Changes in intracellular [Ca²⁺] ([Ca²⁺]_i), high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with IFN-γ with or without the cholinergic agonist carbachol. IFN-γ itself increased [Ca²⁺]_i in rat and human goblet cells and prevented the increase in [Ca²⁺]_i caused by carbachol. Carbachol prevented IFN-γ-mediated increase in [Ca²⁺]_i. This cross-talk between IFN-γ and muscarinic receptors may be partially due to use of the same Ca²⁺_i reservoirs, but also from interaction of signaling pathways proximal to the increase in [Ca²⁺]_i. IFN-γ blocked carbachol-induced high molecular weight glycoconjugate secretion and reduced goblet cell proliferation. We conclude that increased levels of IFN-γ in dry eye disease could explain the lack of goblet cells and mucin deficiency typically found in this pathology. IFN-γ could also function similarly in respiratory and gastrointestinal tracts.

Conjunctival goblet cells play a major role in maintaining the mucus layer of the tear film under physiological conditions as well as in inflammatory diseases like dry eye and allergic conjunctivitis. Resolution of inflammation is mediated by proresolution agonists such as lipoxin A₄ (LXA₄) that can also function under physiological conditions. The purpose of this study was to determine the actions of LXA₄ on cultured rat conjunctival goblet cell mucin secretion, intracellular [Ca²⁺] ([Ca²⁺]_i), and identify signaling pathways activated by LXA₄. ALX/FPR2 (formyl peptide receptor2) was localized to goblet cells in rat conjunctiva and in cultured goblet cells. LXA₄ significantly increased mucin secretion, [Ca²⁺]_i, and extracellular regulated kinase 1/2 (ERK 1/2) activation. These functions were inhibited by ALX/FPR2 inhibitors. Stable analogs of LXA₄ increased [Ca²⁺]_i to the same extent as LXA₄. Sequential addition of either LXA₄ or resolvin D1 followed by the second compound decreased [Ca²⁺]_i of the second compound compared with its initial response. LXA₄ activated phospholipases C, D, and A₂ and downstream molecules protein kinase C, ERK 1/2, and Ca²⁺/calmodulin-dependent kinase to increase mucin secretion and [Ca²⁺]_i. We conclude that conjunctival goblet cells respond to LXA₄ to maintain the homeostasis of the ocular surface and could be a novel treatment for dry eye diseases.