Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets

Abstract

Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype. Prostanoid receptors signal mainly through G proteins and naturally activate signal transduction pathways according to the G protein subtype that they preferentially interact with. This can lead to the activation of sometimes opposing signaling pathways. In addition, prostanoid signaling is often cell-type specific and also the combination of expressed receptors can influence the outcome of the prostanoid impulse. Accordingly, it is assumed that eosinophils and their (patho-)physiological functions are governed by a sensitive prostanoid signaling network. In this review, we specifically focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils. We discuss their significance in allergic and non-allergic diseases and summarize potential targets for drug intervention.

DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

“…PGD 2 is a short‐lived molecule that can rapidly be metabolized to J‐metabolites such as 15‐deoxy‐Δ , Δ‐PGJ 2 (15dPGJ 2 ), which has been reported to have a higher affinity for DP2 than DP1 . 15dPGJ 2 also activates the intracellular peroxisome proliferator‐activated receptor (PPAR)‐γ at micromolar concentrations, thereby inducing apoptosis of eosinophils .…”

“…PGD 2 is the major lipid mediator released by mast cells following crosslinking of allergen‐specific IgE molecules displayed on their surface in sensitized individuals as part of the early allergic reaction . Furthermore, eosinophils, dendritic cells, macrophages, and endothelial cells produce PGD 2 and substantial amounts have been detected in tissues affected by allergic reactions, such as lung, skin, and esophagus . PGD 2 is the ligand for two 7‐transmembrane G protein‐coupled receptors, named D‐type prostanoid (DP) receptor 1 and chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2, also termed DP2), that are co‐expressed on the cell surface of eosinophils .…”

“…We have previously shown in eosinophils and heterologous expression systems that the DP1 receptor augments the signaling and functionality of the DP2 receptor, including intracellular Ca 2+ flux, chemotaxis, and oxidative burst . Defining the role of DP1 on eosinophils might hence contribute to the full understanding of the role of PGD 2 in allergic disease and asthma and explain the limited efficacy of DP2 antagonists in clinical studies . One single report described that activation of DP1 on eosinophils protected them from undergoing apoptosis; whether this resulted in extended life‐span of eosinophils and was due to activation of pro‐survival signaling pathways has still remained unresolved.…”

Human eosinophils and mast cells: Birds of a feather flock together

“…On MCs, PGD 2 triggers the synthesis of Th2 mediators through DP1, while the functions of CRTH2 receptor on MCs are controversial . On eosinophils, DP1 and CRTH2 have some overlapping and cooperative functions, since both receptors are able to induce the egress of eosinophils from bone marrow, and mediate chemotactic activity and production of leukotriene C4 (LTC4) . In asthma models, PGD 2 activation of eosinophils increases their degranulation, mobilization and recruitment in the lungs through CRTH2.…”

“…144 On eosinophils, DP1 and CRTH2 have some overlapping and cooperative functions, since both receptors are able to induce the egress of eosinophils from bone marrow, and mediate chemotactic activity and production of leukotriene C4 (LTC4). 204 In asthma models, PGD 2 activation of eosinophils increases their degranulation, mobilization and recruitment in the lungs through CRTH2. Currently, a CRTH2 antagonist, fevipiprant, is being tested in asthma clinical trials.…”