Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages

• Published in: PloS one Vol. 13; no. 5; p. e0197604
• Main Authors: Zhao, Juanjuan, Okamoto, Yasuo, Asano, Yuya, Ishimaru, Kazuhiro, Aki, Sho, Yoshioka, Kazuaki, Takuwa, Noriko, Wada, Takashi, Inagaki, Yutaka, Takahashi, Chiaki, Nishiuchi, Takumi, Takuwa, Yoh
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2018; Public Library of Science (PLoS)
• Subjects: Animals; Arginase; Biology and Life Sciences; Bleomycin; Bleomycin - toxicity; Bone marrow; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Care and treatment; Cell receptors; Chimeras; Clonal deletion; Cytokines; Development and progression; Disease Models, Animal; Endothelial cells; Epithelial cells; Extracellular matrix; Fibroblasts; Fibrosis; Gene expression; Genetic aspects; Growth factors; Health aspects; Idiopathic Pulmonary Fibrosis - etiology; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Inflammation; Interleukin 13; Interleukin 4; Interleukin-13 - genetics; Interleukin-13 - metabolism; Kinases; Lung diseases; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Medical research; Medicine; Medicine and Health Sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pathogenesis; Pharmacology; Phosphates; Phosphorylation; Physiology; Proteins; Pulmonary fibrosis; Receptors, Lysosphingolipid - deficiency; Receptors, Lysosphingolipid - genetics; Receptors, Lysosphingolipid - metabolism; Research and Analysis Methods; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Signal Transduction; Sphingosine 1-phosphate; Stat6 protein; STAT6 Transcription Factor - metabolism; Transplantation Chimera - genetics; Transplantation Chimera - metabolism; Up-Regulation; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0197604

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.