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The UDP-Glucose Receptor P2RY14 Triggers Innate Mucosal Immunity in the Female Reproductive Tract by Inducing IL-8¹

Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

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 P2RY14 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding was received from Grant-in-Aids from the Japan Society for the Promotion of Science (JSPS) (to T.A., T.M., and Y.Y.) and by grants from Keio Health Counseling Center (to T.M.).

² Address correspondence and reprint requests to Tetsuo Maruyama, Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. E-mail address: tetsuo{at}sc.itc.keio.ac.jp

³ Abbreviations used in this paper: FRT, female reproductive tract; NLR, Nod-like receptor; PAMP, pathogen-associated molecular pattern; AMP, natural antimicrobial peptide; UDP-glucose, uridine 5'-diphosphoglucose; PID, pelvic inflammatory disease; ICR, Imprinting Control Region; PTX, pertussis toxin; siRNA, small interfering RNA; IUD, intrauterine device; KC, keratinocyte-derived cytokine; UDP-GluNAc, UDP-N-acetylglucosamine.

⁴ The online version of this article contains supplemental material.