Activation of the prostaglandin D2 receptor DP2/CRTH2 increases allergic inflammation in mouse.
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.
Spik
Isabelle
I
Unité 547, Institut National de la Santé et de la Recherche Médicale, Institut Fédératif de Recherche 17, Institut Pasteur de Lille, Lille, France.
Brénuchon
Céline
C
Angéli
Véronique
V
Staumont
Delphine
D
Fleury
Sébastien
S
Capron
Monique
M
Trottein
François
F
Dombrowicz
David
D
D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004247:DNA / Q000235:genetics; D003876:Dermatitis, Atopic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004802:Eosinophilia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D015230:Prostaglandin D2 / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D004247:DNA; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor