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 7, 2021.
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