The UDP-glucose receptor P2RY14 triggers innate mucosal immunity in the female reproductive tract by inducing IL-8

Toru Arase, Hiroshi Uchida, Takashi Kajitani, Masanori Ono, Kayoko Tamaki, Hideyuki Oda, Sayaka Nishikawa, Maki Kagami, Takashi Nagashima, Hirotaka Masuda, Hironori Asada, Yasunori Yoshimura, Tetsuo Maruyama

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44 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7074-7084
Number of pages11
JournalJournal of Immunology
Volume182
Issue number11
DOIs
Publication statusPublished - 2009 Jun 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Arase, T., Uchida, H., Kajitani, T., Ono, M., Tamaki, K., Oda, H., Nishikawa, S., Kagami, M., Nagashima, T., Masuda, H., Asada, H., Yoshimura, Y., & Maruyama, T. (2009). The UDP-glucose receptor P2RY14 triggers innate mucosal immunity in the female reproductive tract by inducing IL-8. Journal of Immunology, 182(11), 7074-7084. https://doi.org/10.4049/jimmunol.0900001