Activation of the Prostaglandin D2 Receptor DP2/CRTH2 Increases Allergic Inflammation in Mouse

Abstract

Allergic pathologies are often associated with IgE production, mast cell activation, and eosinophilia. PGD2 is the major eicosanoid, among several inflammatory mediators, released by mast cells. PGD2 binds to two membrane receptors, D prostanoid receptor (DP)1 and DP2, endowed with antagonistic properties. In humans, DP2 is preferentially expressed on type 2 lymphocytes, eosinophils, and basophils and mediates chemotaxis in vitro. Although not yet supported by in vivo studies, DP2 is thought to be important in the promotion of Th2-related inflammation. Herein, we demonstrate that mouse eosinophils express both DP1 and DP2 and that PGD2 exerts in vitro chemotactic effects on eosinophils through DP2 activation. Furthermore, 13,14-dihydro-15-keto-PGD2, a specific DP2 agonist not only increases eosinophil recruitment at inflammatory sites but also the pathology in two in vivo models of allergic inflammation: atopic dermatitis and allergic asthma. By contrast, DP1 activation tends to ameliorate the pathology in asthma. Taken together, these results support the hypothesis that DP2 might play a critical role in allergic diseases and underline the interest of DP2 antagonists in human therapy.

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

“…Activation of DP receptor leads to a G smediated increase in intracellular cAMP and agonist-induced Ca 2ϩ flux (20). Moreover, PGD 2 signaling through CRTH2 coupled with the G i -type G protein leads to a decrease in cAMP, which subsequently stimulates intracellular Ca 2ϩ in various cell types (21). Because increases in intracellular Ca 2ϩ levels are often associated with immune-cell activation, the chemotactic effects of CRTH2 are in agreement with its reported signaling pattern (22).…”

TSG-6 Protein Is Crucial for the Development of Pulmonary Hyaluronan Deposition, Eosinophilia, and Airway Hyperresponsiveness in a Murine Model of Asthma

“…Interestingly, PGD 2 and its high affinity receptors DP1 and CRTH2 (chemoattractant-homologous receptor expressed on Th2 cells) have been shown to be crucial for the promotion and maintenance of allergic responses (51)(52)(53)(54)(55). Importantly, although PGD 2 promotes inflammatory responses through its CRTH2 receptor, which is selectively expressed on eosinophils, Th2 T cells, and basophils (54,55), PGD 2 also has anti-inflammatory and inhibitory effects on neutrophils (56,57).…”

Prostaglandin D2 DP1 receptor is beneficial in ischemic stroke and in acute exicitotoxicity in young and old mice

“…Activation of DP1 receptors is primarily associated with anti-inflammatory effects, but proinflammatory effects of DP1 also have been described (Matsuoka et al 2000;Hammad et al 2003;Angeli et al 2004;Spik et al 2005). It has been reported that PGD 2 induces nerve growth factor and brain-derived neurotrophic factor (Toyomoto et al 2004).…”