Abstract
PGD2 has long been implicated in allergic diseases. Recent cloning of a second PGD2 receptor, DP2 (also known as CRTh2), led to a greater understanding of the physiological and pathophysiological implications of PGD2. PGD2 signaling through DP1 and DP2 mediates different and often opposite effects in many cell types of the immune system. Although mast cells (MC) are the largest source of PGD2 in the body, there is little information about their potential expression of DP2 and its functional significance. In this study, we show that tissue MC in human nasal polyps express DP2 protein, and that human MC lines and primary cultured human MC express mRNA as well as protein of DP2. By immunohistochemistry, we detected that 34% of MC in human nasal polyps expressed DP2. In addition, flow cytometry showed that 87% of the LAD2 human MC line and 98% of primary cultured human MC contained intracellular DP2. However, we could not detect surface expression of DP2 on human MC by single cell analysis using imaging flow cytometry. Blocking of endogenous PGD2 production with aspirin did not induce surface expression of DP2 in human MC. Two DP2 selective agonists, DK-PGD2 and 15R-15-methyl PGD2 induced dose-dependent intracellular calcium mobilization that was abrogated by pertussis toxin, but not by three DP2 selective antagonists. MC mediator release including degranulation was not affected by DP2 selective agonists. Thus, human MC express DP2 intracellularly rather than on their surface, and the function of DP2 in human MC is different than in other immune cells such as Th2 cells, eosinophils and basophils where it is expressed on the cell surface and induces Th2 cytokine and/or granule associated mediator release. Further studies to elucidate the role of intracellular DP2 in human MC may expand our understanding of this molecule and provide novel therapeutic opportunities.
Highlights
Mast cells (MC) are tissue-resident cells derived from bone marrow progenitors
Expression of PGD2 receptors in human MC Despite increasing evidence for DP2, known as CRTh2, expression and function in various cell types [27,40,41], little is known about expression and function of DP2 in MC [5]
PGD2 is the predominant prostanoid produced by activated MC and plays important roles in regulation of allergic inflammation, host defense, and innate and adaptive immune responses
Summary
Mast cells (MC) are tissue-resident cells derived from bone marrow progenitors. They are widely distributed throughout the body, performing multiple tasks in different locations and functional settings. MC are primary effector cells of allergic inflammation following IgE cross-linking and they have diverse roles in angiogenesis, wound healing, tissue remodeling, regulation of inflammation, host defense, and innate and adaptive immune responses [1,2,3,4] Along with mediators such as histamine and proteases in the granules, and de novo synthesized cytokines and chemokines, activated MC produce an abundance of prostaglandin (PG) D2 and leukotriene (LT) C4 [5,6]. DP2 [ known as CRTh2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), GPR44, and CD294] is a GPCR of the formylmethionylleucylphenylalanine receptor subfamily with a primary amino acid sequence homology to chemokine receptors It signals with PTX-sensitive Gi proteins that suppress adenylate cyclase and decrease intracellular cAMP levels, but induces intracellular Ca2+ mobilization in response to PGD2 [20,26,27]. Human and/or mouse eosinophils, basophils, macrophages and dendritic cells express DP2, and DP2 signaling causes chemotaxis and activation of these cells [18,19,20,21,22,23,24,26,29,30]
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