The UDP-glucose receptor P2RY14 triggers innate mucosal immunity in the female reproductive tract by inducing IL-8.
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.
Arase
Toru
T
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
Uchida
Hiroshi
H
Kajitani
Takashi
T
Ono
Masanori
M
Tamaki
Kayoko
K
Oda
Hideyuki
H
Nishikawa
Sayaka
S
Kagami
Maki
M
Nagashima
Takashi
T
Masuda
Hirotaka
H
Asada
Hironori
H
Yoshimura
Yasunori
Y
Maruyama
Tetsuo
T
D000818:Animals; D002633:Chemotaxis; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005836:Genitalia, Female / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D009092:Mucous Membrane / Q000276:immunology*; D009504:Neutrophils / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058470:Receptors, Purinergic P2Y; D015854:Up-Regulation / Q000235:genetics*; D014532:Uridine Diphosphate Glucose / Q000494:pharmacology; D014599:Uterus
D016209:Interleukin-8; C509795:P2ry14 protein, mouse; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y; D014532:Uridine Diphosphate Glucose