P2Y 6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals

Hideya Uratsuji, Yayoi Tada, Tomohiko Kawashima, Masahiro Kamata, Carren Sy Hau, Yoshihide Asano, Makoto Sugaya, Takafumi Kadono, Akihiko Asahina, Shinichi Sato, Kunihiko Tamaki

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y 6 receptors, stimulated normal human keratinocytes (NHK) to produce IL-1α, IL-8/CXCL8, and IL-6. P2Y 6 receptor expression increased in MSU-stimulated NHK. Both P2Y 6-specific antagonist and P2Y 6 antisense oligonucleotides significantly inhibited the production of IL-1α, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y 6-specific antagonist completely inhibited the MSU-induced production of IL-1β by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y 6-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y 6receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.

Original languageEnglish
Pages (from-to)436-444
Number of pages9
JournalJournal of Immunology
Volume188
Issue number1
DOIs
Publication statusPublished - 2012 Jan 1

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