The UDP-Glucose Receptor P2RY14 Triggers Innate Mucosal Immunity in the Female Reproductive Tract by Inducing IL-8
The UDP-Glucose Receptor P2RY14 Triggers Innate Mucosal Immunity in the Female Reproductive Tract by Inducing IL-8
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DOI：
10.4049/jimmunol.0900001
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
Maruyama, Tetsuo
中科院分区：
文献类型：
--
作者：
Arase, Toru;Uchida, Hiroshi;Maruyama, Tetsuo
先天性粘膜免疫应答，包括通过Toll样受体识别病原体相关分子模式，在预防女性生殖道（FRT）感染中发挥重要作用。在炎症和机械应力期间，受损细胞释放核苷酸，包括ATP和尿苷5 '-二磷酸葡萄糖（UDP-葡萄糖）。我们在这份报告中表明，P2 RY 14，UDP-葡萄糖的膜受体，是专门在上皮细胞中表达，但不是基质，在人类和小鼠的FRT。P2 RY 14和几种促炎细胞因子，如IL-8，在盆腔炎患者的尿道中上调。UDP-葡萄糖通过P2 RYI 4刺激人子宫内膜上皮细胞而不是基质细胞产生IL-8。此外，UDP-葡萄糖增强中性粒细胞的趋化性，在存在的人子宫内膜上皮细胞系在IL-8依赖的方式。UDP-葡萄糖进入小鼠子宫的管理诱导巨噬细胞炎性蛋白-2和角质形成细胞衍生的细胞因子的表达，这两种小鼠趋化因子是IL-8的功能同源物，并增加子宫内膜中性粒细胞的募集。通过小干扰RNA基因沉默减少P2 RY 14的表达可减弱LPS或UDP葡萄糖诱导的小鼠子宫白细胞增多。这些结果表明，UDP-葡萄糖及其受体P2 RY 14是能够在FRT中触发先天性粘膜免疫应答的关键前线参与者，从而绕过病原体相关分子模式的识别。我们的发现将显著影响通过靶向P2 RY 14调节粘膜免疫的疗法的策略设计。免疫学杂志，2009，182：7074-7084.
Innate mucosal immune responses, including recognition of pathogen-associated molecular patterns through Toll-like receptors, play an important role in preventing infection in the female reproductive tract (FRT). Damaged cells release nucleotides, including ATP and uridine 5'-diphosphoglucose (UDP-glucose), during inflammation and mechanical stress. We show in this report that P2RY14, a membrane receptor for UDP-glucose, is exclusively expressed in the epithelium, but not the stroma, of the FRT in humans and mice. P2RY14 and several proinflammatory cytokines, such as IL-8, are up-regulated in the endometria of patients with pelvic inflammatory disease. UDP-glucose stimulated IL-8 production via P2RYI4 in human endometrial epithelial cells but not stromal cells. Furthermore, UDP-glucose enhanced neutrophil chemotaxis in the presence of a human endometrial epithelial cell line in an IL-8-dependent manner. Administration of UDP-glucose into the mouse uterus induced expression of macrophage inflammatory protein-2 and keratinocyte-derived cytokine, two murine chemokines that are functional homologues of IL-8, and augmented endometrial neutrophil recruitment. Reduced expression of P2RY14 by small interfering RNA gene silencing attenuated LPS- or UDP-glucose-induced leukocytosis in the mouse uterus. These results suggest that UDP-glucose and its receptor P2RY14 are key front line players able to trigger innate mucosal immune responses in the FRT bypassing the recognition of pathogen-associated molecular patterns. Our findings would significantly impact the strategic design of therapies to modulate mucosal immunity by targeting P2RY14. The Journal of Immunology, 2009, 182: 7074-7084.