CRTH2 and D-Type Prostanoid Receptor Antagonists as Novel Therapeutic Agents for Inflammatory Diseases

Accumulation of type 2 T helper (Th2) lymphocytes and eosinophils is a hallmark of bronchial asthma and other allergic diseases, and it is believed that these cells play a crucial pathogenic role in allergic inflammation. Thus, Th2 cells and eosinophils are currently considered a major therapeutic target in allergic diseases and asthma. However, drugs that selectively target the accumulation and activation of Th2 cells and eosinophils in tissues are unavailable so far. Prostaglandin (PG)D 2 is a key mediator in various inflammatory diseases including allergy and asthma. It is generated by activated mast cells after allergen exposure and subsequently orchestrates the recruitment of inflammatory cells to the tissue. PGD 2 induces the chemotaxis of Th2 cells, basophils and eosinophils, stimulates cytokine release from these cells and prolongs their survival, and might hence indirectly promote IgE production. PGD 2 mediates its biologic functions via 2 distinct G protein-coupled receptors, D-type prostanoid receptor (DP), and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). DP and CRTH2 receptors are currently being considered as highly promising therapeutic targets for combating allergic diseases and asthReceived: April 13, 2010 Accepted: April 13, 2010 Published online: June 16, 2010 Univ. Prof. Dr. Akos Heinemann Institute of Experimental and Clinical Pharmacology, Medical University of Graz Universitätsplatz 4 AT–8010 Graz (Austria) Tel. +43 316 380 4508, Fax +43 316 380 9645, E-Mail akos.heinemann @ medunigraz.at © 2010 S. Karger AG, Basel 0031–7012/10/0856–0372$26.00/0 Accessible online at: www.karger.com/pha PGD 2 Receptors as Therapeutic Targets Pharmacology 2010;85:372–382 373 frequently ineffective or, like corticosteroids, might have serious side effects [1, 2] . Therefore, demand persists for additional treatments of allergic diseases, particularly for those patients who need to avoid corticosteroids (e.g. children), and those who are insufficiently treated by standard therapeutic regimens. In the case of bronchial asthma, these patients rely mainly on bronchodilator therapy and are at risk of suffering both from side effects of these drugs and uncontrolled pulmonary inflammation leading to airway remodeling [3] . The discovery of the orphan G protein-coupled receptor GPR44, its expression pattern (basophils, eosinophils and type 2 T helper, Th2, cells) [4] and its ensuing deorphanization as a receptor for the mast cell-derived mediator prostaglandin (PG)D 2 [5] has fueled additional research in the field. This novel receptor, meanwhile termed ‘chemoattractant receptor-homologous molecule expressed on Th2 cells’ (CRTH2), has thus provided an innovative and promising target for antiinflammatory drug development. Role of PGD 2 in Allergic Inflammation Like other prostanoids, PGD 2 is synthesized by phospholipase A 2 , cyclooxygenase and specific terminal synthases upon activation of cells by different stimuli such as allergens, oxidative stress or cytokines. PGD 2 is the major mast cell product that is released during anaphylaxis [6, 7] and substantial evidence has accumulated in the last few years that PGD 2 might be involved in the initiation and perpetuation of allergic inflammation. However, PGD 2 is produced in significant amounts also by dendritic cells, macrophages, eosinophils, Th2 cells and endothelial cells [8–14] . A prominent contribution of PGD 2 to the late-phase allergic reaction is, on the one hand, suggested by enhanced eosinophilic lung inflammation and cytokine release in transgenic mice overexpressing PGD synthase [15] . Moreover, PGD 2 enhances leukotriene (LT) C 4 synthesis by eosinophils during allergic inflammation [16] . Conversely, an inhibitor of hematopoietic PGD synthase attenuates the antigen-induced production of PGD 2 and ameliorates airway inflammation in vivo in mice [17] . Interestingly, the biosynthesis of PGD 2 increases after the intake of cyclooxygenase inhibitors in aspirin-intolerant patients [18–20] . The resulting imbalance between PGD 2 and PGE 2 has been suggested to favor the development of asthma and nasal polyposis [21] . On the other hand, PGD 2 has been suggested to play a beneficial role in the resolution phase of inflammation by controlling Th1-mediated mechanisms [22, 23] . Receptors for PGD 2 The biological effects of PGD 2 are, in principle, mediated by two distinct G protein-coupled receptors, D-type prostanoid receptor (DP) and CRTH2. Moreover, at higher concentrations, PGD 2 is a ligand for the thromboxane (TX) receptor, which mediates the bronchoconstrictor effect of PGD 2 [24, 25] . Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells CRTH2, also known as DP 2 , GPR44 or CD294, has initially been found on Th2 cells, eosinophils and basophils [4] , and mediates their chemotaxis towards PGD 2 [5, 26] . However, the CRTH2 receptor is activated not only by PGD 2 but also by several PGD 2 metabolites – including 13,14-dihydro-15-keto-PGD 2 , PGJ 2 , 12 PGJ 2 , 12 PGD 2 , 9 ,11 -PGF 2 and 15-deoxy-PGJ 2 [27–30] –, by PGF 2 [30] , a thromboxane metabolite, 11-dehydroTXB 2 [31] , and also by the precursor of all 2-series PG and TX, PGH 2 [32] . In animal models, exogenously administered CRTH2 agonists can induce eosinophil infiltration into the lungs and skin, and aggravate the pathology of allergic responses [33–35] . Moreover, several experimental studies in mice have shown that CRTH2 antagonists can ameliorate allergen-induced cutaneous, pulmonary and upper respiratory inflammation [36–41] . In humans, sequence variants of the gene encoding CRTH2 are associated with asthma and allergic phenotypes [42] . In addition, recent data suggest that CRTH2 is also expressed on monocytes [43] and macrophages, and mediates their migration induced by PGD 2 and endotoxin [8, 44] . Strikingly, PGD 2 levels in bronchoalveolar lavage fluid of patients with chronic obstructive pulmonary disease correlate inversely with lung function [45] . Therefore, using CRTH2 antagonists is currently being considered as a highly promising approach to the treatment of allergic diseases and asthma. Interestingly, a CRTH2 antagonist is currently being evaluated in phase II trials in patients with chronic obstructive pulmonary disease (clinical trial registration No. NCT00690482, NCT00766415). CRTH2 signals through G i proteins, leading to inhibition of cAMP formation and increases in intracellular Ca 2+ [5] . In eosinophils, however, we observed that CRTH2 stimulation leads to pertussis-toxin-insensitive activation of phosphatidylinositol 3-kinase (PI3K), phospholipase C, p38 mitogen-activated protein kinase (MAPK) and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase [46] . These pathways mediate eosinophil shape change, actin polymerization