CRTH2 is a prominent effector in contact hypersensitivity-induced neutrophil inflammation.
Chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes, CRTH2, is a cognate receptor for prostaglandin (PG) D(2) and, in humans, is suggested to play a functional role in Th2-dependent allergic inflammation. While peripheral blood leukocytes expressing high levels of surface CRTH2 have been detected in disease, little is known of the functional significance of CRTH2 in disease etiology. We have utilized a Th2-dependent murine model of FITC-induced contact hypersensitivity to assess the role, if any, CRTH2-PGD(2) may play in the elicitation or maintenance of such pathobiology. Expression of both PGD(2) and CRTH2 in lesional skin was paralleled by the release of the chemoattractants LTB(4) and the chemokine KC, as well as a profuse dermal neutrophilic and eosinophilic infiltrate, closely paralleling the acute inflammatory pathology observed in human atopic dermatitis. A small molecule CRTH2 antagonist, but not a selective PGD(2)R (DP) receptor antagonist, was able to completely abrogate these responses. Inflammatory cascades mediated by CRTH2 ligation may therefore represent an important early step in the elicitation and maintenance of Th2-dependent skin inflammation.
Takeshita
Keisuke
K
Bayer Yakuhin, Ltd., Research Center Kyoto, Respiratory Disease Research, 6-5-1-3, Kunimidai, Kizu-cho, Soraku-gun, 619-0216 Kyoto, Japan.
Yamasaki
Tsugiko
T
Nagao
Koichi
K
Sugimoto
Hiromi
H
Shichijo
Michitaka
M
Gantner
Florian
F
Bacon
Kevin B
KB
D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000276:immunology* / Q000473:pathology; D003876:Dermatitis, Atopic / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007975:Leukotriene B4 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D015230:Prostaglandin D2 / Q000276:immunology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000276:immunology*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013449:Sulfonamides / Q000008:administration & dosage; D018418:Th2 Cells / Q000276:immunology*
D002227:Carbazoles; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D010975:Platelet Aggregation Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C074302:keratinocyte-derived chemokines; D007975:Leukotriene B4; C063119:ramatroban; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor