Department of Dermatology, University of Tokyo, Tokyo, Japan.
J Immunol. 2012 Jan 1;188(1):436-44. doi: 10.4049/jimmunol.1003746. Epub 2011 Nov 18.
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(6) receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.
当单钠尿酸盐 (MSU) 晶体在组织中沉淀并通过吞噬细胞（如单核细胞）诱导急性炎症时，痛风就会发生在高尿酸血症的个体中。MSU 晶体已在皮肤病中得到证实，如痛风石或银屑病；然而，MSU 晶体在皮肤中的重要性尚完全未知。在这项研究中，我们发现 MSU 晶体通过 P2Y(6) 受体刺激正常人角质形成细胞 (NHK) 产生 IL-1α、IL-8/CXCL8 和 IL-6。在 MSU 刺激的 NHK 中，P2Y(6) 受体表达增加。P2Y(6) 特异性拮抗剂和 P2Y(6) 反义寡核苷酸均显著抑制 NHK 产生 IL-1α、IL-8/CXCL8 和 IL-6。同样，P2Y(6) 特异性拮抗剂完全抑制了 THP-1 细胞（一种人类单核细胞系）中 MSU 诱导的 IL-1β 的产生。值得注意的是，P2Y(6) 特异性拮抗剂可显著减少小鼠气囊和腹膜炎模型中的中性粒细胞浸润。因此，这些结果表明 P2Y(6) 受体信号通路可能是 MSU 相关炎症性疾病（如痛风石）的潜在治疗靶点。
