P2Y6 Receptor Signaling Pathway Mediates Inflammatory Responses Induced by Monosodium Urate Crystals
P2Y6 Receptor Signaling Pathway Mediates Inflammatory Responses Induced by Monosodium Urate Crystals
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DOI：
10.4049/jimmunol.1003746
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发表时间：
2012-01-01
影响因子：
4.4
通讯作者：
Tamaki, Kunihiko
中科院分区：
文献类型：
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作者：
Uratsuji, Hideya;Tada, Yayoi;Tamaki, Kunihiko
痛风发生在高尿酸血症患者中，当尿酸单钠(MSU)晶体在组织中沉淀并通过单核细胞等吞噬细胞引起急性炎症时。MSU晶体已被证明用于皮肤病，如皮肤性痛风或牛皮癣；然而，MSU晶体在皮肤中的重要性完全不清楚。在本研究中，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。MSU刺激NHK后，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MSU诱导的人单核细胞系THP-1细胞产生IL-1β。值得注意的是，P2Y(6)特异性拮抗剂显著减少了中性粒细胞在小鼠气囊和腹膜炎模型中的流入。因此，这些结果表明，P2Y(6)受体信号通路可能是治疗MSU相关炎症性疾病的潜在靶点，例如痛风。免疫学杂志，2012,188：436-444。
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-1 alpha, 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-1 alpha, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y(6)-specific antagonist completely inhibited the MSU-induced production of IL-1 beta 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. The Journal of Immunology, 2012, 188: 436-444.