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Hyperglycemia Triggered S1P/S1PR3 Signaling Worsens Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization.

Liver Transplantation 2019 April 11
BACKGROUND: 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.

METHODS: In vivo, we enrolled diabetic patients with hepatic benign disease who had liver resection and used streptozotocin induced hyperglycemia mice or normal mice establish liver IRI model. In vitro, bone marrow-derived macrophages (BMDMs) were differentiated in high-glucose (30 m M) or low-glucose (5 m M) conditions for 7 days. Expression of S1P/S1PRs was analyzed in liver and BMDMs. We investigated the function/molecular mechanisms by which S1P/S1PRs may influence hyperglycemia-related liver IRI.

RESULTS: S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with streptozotocin-induced diabetes. S1PR3, but not S1PR1 and S1PR2, was 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 but lower levels of M2 markers 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 inflammation.

CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.

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