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Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages.
Zhao, Juanjuan; Okamoto, Yasuo; Asano, Yuya; Ishimaru, Kazuhiro; Aki, Sho; Yoshioka, Kazuaki; Takuwa, Noriko; Wada, Takashi; Inagaki, Yutaka; Takahashi, Chiaki; Nishiuchi, Takumi; Takuwa, Yoh.
Afiliación
  • Zhao J; Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Okamoto Y; Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Asano Y; Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Ishimaru K; Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Aki S; Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Yoshioka K; Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Takuwa N; Department of Physiology, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Wada T; Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, Ishikawa, Japan.
  • Inagaki Y; Department of Nephrology and Laboratory Medicine, Kanazawa University School of Medicine, Ishikawa, Japan.
  • Takahashi C; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Kanagawa, Japan.
  • Nishiuchi T; Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan.
  • Takuwa Y; Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Ishikawa, Japan.
PLoS One ; 13(5): e0197604, 2018.
Article en En | MEDLINE | ID: mdl-29782549
Idiopathic pulmonary fibrosis is a devastating disease with poor prognosis. The pathogenic role of the lysophospholipid mediator sphingosine-1-phosphate and its receptor S1PR2 in lung fibrosis is unknown. We show here that genetic deletion of S1pr2 strikingly attenuated lung fibrosis induced by repeated injections of bleomycin in mice. We observed by using S1pr2LacZ/+ mice that S1PR2 was expressed in alveolar macrophages, vascular endothelial cells and alveolar epithelial cells in the lung and that S1PR2-expressing cells accumulated in the fibrotic legions. Bone marrow chimera experiments suggested that S1PR2 in bone marrow-derived cells contributes to the development of lung fibrosis. Depletion of macrophages greatly attenuated lung fibrosis. Bleomycin administration stimulated the mRNA expression of the profibrotic cytokines IL-13 and IL-4 and the M2 markers including arginase 1, Fizz1/Retnla, Ccl17 and Ccl24 in cells collected from broncho-alveolar lavage fluids (BALF), and S1pr2 deletion markedly diminished the stimulated expression of these genes. BALF cells from bleomycin-administered wild-type mice showed a marked increase in phosphorylation of STAT6, a transcription factor which is activated downstream of IL-13, compared with saline-administered wild-type mice. Interestingly, in bleomycin-administered S1pr2-/- mice, STAT6 phosphorylation in BALF cells was substantially diminished compared with wild-type mice. Finally, pharmacological S1PR2 blockade in S1pr2+/+ mice alleviated bleomycin-induced lung fibrosis. Thus, S1PR2 facilitates lung fibrosis through the mechanisms involving augmentation of IL-13 expression and its signaling in BALF cells, and represents a novel target for treating lung fibrosis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-13 / Receptores de Lisoesfingolípidos / Fibrosis Pulmonar Idiopática / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2018 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-13 / Receptores de Lisoesfingolípidos / Fibrosis Pulmonar Idiopática / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2018 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos