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Hyperglycemia Triggered S1P/S1PR3 Signaling Worsens Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization
43 Pages Posted: 20 Sep 2018More...
Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI) but the underlying mechanism remains elusive. Sphingosine 1-phosphate (S1P)/S1P receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we clarify whether and how S1P/S1PRs are involved in hyperglycemia-related liver IRI.S1P levels were significantly higher in liver tissues from patients with diabetes mellitus and mice with streptozotocin-induced diabetes. S1PR3, but not S1PR1 and S1PR2, was specifically activated in liver tissues and KCs under hyperglycemic conditions. S1PR3 antagonist CAY-10444 attenuated hyperglycemia-related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic liver expressed higher levels of M1 markers [NO synthase 2 and phosphorylated signal transducer and activator of transcription (p-STAT)1] but lower levels of M2 markers (arginase, mannose receptor C type 1, p-STAT3, and p-STAT6) at baseline and post-IR. Dual-immunofluorescence staining showed that hyperglycemia promoted M1 (CD68/CD86) differentiation and inhibited M2 (CD68/CD206) differentiation. Importantly, CAY10444 reversed hyperglycemia-modulated M1/M2 polarization. In vitro, high glucose(HG) concentrations also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with low glucose(LG) concentrations in bone marrow-derived macrophages (BMDMs). In contrast, S1PR3 knockdown significantly retrieved hyperglycemia-modulated M1/M2 polarization, and attenuated Toll-like-receptor-4-related inflammation. Administration of HG-cultured BMDMs worsened liver IRI, which was rescued by S1PR3 knockdown. Our study reveals that hyperglycemia specifically triggers S1P/S1PR3 signaling and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization, which may represent an effective therapeutic strategy for liver IRI in diabetes.
Funding: This study was supported by the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, the Priority Academic Program Development of Jiangsu Higher Education Institutions, the National Natural Science Foundation of China (81400650, 814700901, 81273261, and 81270583).
Declaration of Interest: All authors declare no conflict of interests.
Ethical Approval: All mice received humane care and all procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee of Nanjing Medical University.
Keywords: Hyperglycemia; S1P; S1PR3, M1/M2 polarization; Inflammation; Ischemia reperfusion injury
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