Hyperglycemia-Triggered S1P/SIPR3signaling Exacerbates Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization
1Department of Liver Surgery/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles.
Meeting: 2018 American Transplant Congress
Abstract number: A81
Keywords: Hypercalcemia, Ischemia
Session Information
Session Name: Poster Session A: Innate Immunity; Chemokines, Cytokines, Complement
Session Type: Poster Session
Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background and Aims: Hyperglycemia/Diabetes is an adverse risk factor for hepatic ischemia/reperfusion injury (IRI) during liver transplantation or hepatectomy; however, the underlying mechanism remains unclear.Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR1-3) system has been implicated in the pathological of variety organs damage. The aim of this study was to clarify whether and how (S1P)/S1P receptor (S1PR1-3) system is involved in hyperglycemia-exacerbated liver IRI.
Method: Diabetic patients and streptozotocin (STZ)-induced diabetic mice were involved in vivo. Bone marrow-derived macrophages (BMDMs) were used in vitro.
Results: S1P-S1PR3, not S1P-S1PR1 and S1P-S1PR2 signaling pathway, was specifically activated in liver tissues and Kuppfer cells (KCs) from diabetic patients and STZ-induced diabetic mice. CAY-10444, as an antagonist of S1PR3, effectively attenuated hyperglycemia-exacerbated liver IRI based on hepatic biochemistry, histological liver damage, and inflammatory responses. Interestingly, diabetic mice administrated with CAY-10444 expressed higher levels of M2 markers and lower levels of M1 markers compared with untreated diabetic mice. What's more, diabetic mice administrated with CAY-10444 also enhanced Stat3- and Stat6-signaling pathway activation. In vitro, hyperglycemia triggered S1P-S1PR3 signaling, promoted TLRs activation, and enhanced synthesis and release of pro-inflammatory cytokines in BMDMs. S1PR3 knockdown (KD) expressed lower levels of M1 markers and produced lower TNF-a, IL-6 but higher IL-10 in response to TLR ligands compared with the controls. In addition, S1PR3 KD had also enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation.
Conclusion: This study demonstrates hyperglycemia specifically triggers S1P-S1PR3 signaling, promotes inflammatory responses, and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization.
CITATION INFORMATION: Rao J., Hu Y., Yang C., Yang S., Cheng F., Zhang F., Wang X., Zhai Y., Lu L. Hyperglycemia-Triggered S1P/SIPR3signaling Exacerbates Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Rao J, Hu Y, Yang C, Yang S, Cheng F, Zhang F, Wang X, Zhai Y, Lu L. Hyperglycemia-Triggered S1P/SIPR3signaling Exacerbates Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization [abstract]. https://atcmeetingabstracts.com/abstract/hyperglycemia-triggered-s1p-sipr3signaling-exacerbates-liver-ischemia-reperfusion-injury-by-regulating-m1-m2-polarization/. Accessed May 13, 2025.« Back to 2018 American Transplant Congress