Prostaglandin D2 Plays an Essential Role in Chronic Allergic Inflammation of the Skin via CRTH2 Receptor

• Published in: The Journal of immunology (1950) 2006-08, Vol.177 (4), p.2621-2629
• Main Authors: Satoh, Takahiro, Moroi, Rie, Aritake, Kosuke, Urade, Yoshihiro, Kanai, Yasumasa, Sumi, Koji, Yokozeki, Hiroo, Hirai, Hiroyuki, Nagata, Kinya, Hara, Toshifumi, Utsuyama, Masanori, Hirokawa, Katsuiku, Sugamura, Kazuo, Nishioka, Kiyoshi, Nakamura, Masataka
• Format: Article
• Language: English
• Subjects: Animals; Chronic Disease; Dermatitis, Allergic Contact - genetics; Dermatitis, Allergic Contact - immunology; Dermatitis, Allergic Contact - metabolism; Disease Models, Animal; Female; Immunoglobulin E - physiology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin D2 - metabolism; Prostaglandin D2 - physiology; Receptors, Immunologic - deficiency; Receptors, Immunologic - genetics; Receptors, Immunologic - physiology; Receptors, Prostaglandin - deficiency; Receptors, Prostaglandin - genetics; Receptors, Prostaglandin - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.177.4.2621

PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.