PMID- 30972941 OWN - NLM STAT- MEDLINE DCOM- 20200821 LR - 20200821 IS - 1527-6473 (Electronic) IS - 1527-6465 (Print) IS - 1527-6465 (Linking) VI - 25 IP - 7 DP - 2019 Jul TI - Hyperglycemia-Triggered Sphingosine-1-Phosphate and Sphingosine-1-Phosphate Receptor 3 Signaling Worsens Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization. PG - 1074-1090 LID - 10.1002/lt.25470 [doi] AB - Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI), but the underlying mechanism for the aggravation remains elusive. Sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we discuss whether and how S1P/S1PRs are involved in hyperglycemia-related liver IRI. For our in vivo experiment, we enrolled diabetic patients with benign hepatic disease who had liver resection, and we used streptozotocin (STZ)-induced hyperglycemic mice or normal mice to establish a liver IRI model. In vitro bone marrow-derived macrophages (BMDMs) were differentiated in high-glucose (HG; 30 mM) or low-glucose (LG; 5 mM) conditions for 7 days. The expression of S1P/S1PRs was analyzed in the liver and BMDMs. We investigated the functional and molecular mechanisms by which S1P/S1PRs may influence hyperglycemia-related liver IRI. S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with STZ-induced diabetes. S1PR3, but not S1PR1 or S1PR2, was activated in liver tissues and Kupffer cells under hyperglycemic conditions. The S1PR3 antagonist CAY10444 attenuated hyperglycemia-related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic livers expressed higher levels of M1 markers but lower levels of M2 markers at baseline and after ischemia/reperfusion. 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. HG concentrations in vitro also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with LG concentrations in BMDMs. In contrast, S1PR3 knockdown significantly retrieved hyperglycemia-modulated M1/M2 polarization and attenuated inflammation. In conclusion, 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. CI - Copyright (c) 2019 The Authors. Liver Transplantation published by Wiley Periodicals Inc., on behalf of the American Association for the Study of Liver Diseases. FAU - Hu, Yuanchang AU - Hu Y AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. FAU - Yang, Chao AU - Yang C AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. FAU - Shen, Gefengqiang AU - Shen G AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. FAU - Yang, Shikun AU - Yang S AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. FAU - Cheng, Xuyu AU - Cheng X AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. FAU - Cheng, Feng AU - Cheng F AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. FAU - Rao, Jianhua AU - Rao J AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. FAU - Wang, Xuehao AU - Wang X AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190603 PL - United States TA - Liver Transpl JT - Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society JID - 100909185 RN - 0 (CAY10444) RN - 0 (Lysophospholipids) RN - 0 (S1pr3 protein, mouse) RN - 0 (Sphingosine-1-Phosphate Receptors) RN - 0 (Thiazolidines) RN - 0 (sphingosine-1-phosphate receptor-3, human) RN - 26993-30-6 (sphingosine 1-phosphate) RN - 5W494URQ81 (Streptozocin) RN - NGZ37HRE42 (Sphingosine) SB - IM MH - Aged MH - Animals MH - Diabetes Mellitus, Experimental/blood/chemically induced/complications/immunology MH - Diabetes Mellitus, Type 1/complications/immunology MH - Female MH - Humans MH - Hyperglycemia/blood/*immunology MH - Liver/immunology/pathology/surgery MH - Liver Diseases/*immunology/pathology/surgery MH - Liver Transplantation/*adverse effects MH - Lysophospholipids/metabolism MH - Macrophages/*immunology/metabolism MH - Male MH - Mice MH - Middle Aged MH - Reperfusion Injury/*immunology/pathology/prevention & control MH - Signal Transduction/immunology MH - Sphingosine/analogs & derivatives/metabolism MH - Sphingosine-1-Phosphate Receptors/antagonists & inhibitors/*metabolism MH - Streptozocin/toxicity MH - Thiazolidines/administration & dosage PMC - PMC6617772 EDAT- 2019/04/12 06:00 MHDA- 2020/08/22 06:00 PMCR- 2019/07/10 CRDT- 2019/04/12 06:00 PHST- 2018/09/24 00:00 [received] PHST- 2019/04/04 00:00 [accepted] PHST- 2019/04/12 06:00 [pubmed] PHST- 2020/08/22 06:00 [medline] PHST- 2019/04/12 06:00 [entrez] PHST- 2019/07/10 00:00 [pmc-release] AID - LT25470 [pii] AID - 10.1002/lt.25470 [doi] PST - ppublish SO - Liver Transpl. 2019 Jul;25(7):1074-1090. doi: 10.1002/lt.25470. Epub 2019 Jun 3.