Indomethacin inhibits eosinophil migration to prostaglandin D 2 : therapeutic potential of CRTH 2 desensitization for eosinophilic pustular folliculitis

• Published in: Immunology 2013-09, Vol.140 (1), p.78-86
• Main Authors: Kataoka, Naoko, Satoh, Takahiro, Hirai, Aiko, Saeki, Kazumi, Yokozeki, Hiroo
• Format: Article
• Language: English
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12112

Indomethacin is a cyclo‐oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non‐steroidal anti‐inflammatory drugs, it is a potent agonist of chemoattractant receptor‐homologous molecule expressed on T helper type 2 cells ( CRTH 2), a receptor for prostaglandin D 2 ( PGD 2 ). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD 2 and indomethacin through CRTH 2 receptors. Pre‐treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD 2 and, to a much lesser extent, to eotaxin ( CCL 11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH 2 and CCR 3, respectively, by agonistic effects of indomethacin on CRTH 2. Indomethacin also cancelled a priming effect of Δ 12 ‐ PGJ 2 , a plasma metabolite of PGD 2 , on eosinophil chemotaxis to eotaxin. Indomethacin down‐modulated cell surface expression of both CRTH 2 and CCR 3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin‐type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD 2 ‐ CRTH 2 signals play major roles by reducing eosinophil responses to PGD 2 .