Nakamura K, Zarrinpar A, Sosa RA, Fujii T, Kageyama S, Kupiec-Weglinski JW, Datta N, Busuttil RW, Ke B, Reed EF
Hepatic ischemia-reperfusion injury (IRI), an inevitable antigen-independent inflammation response in cadaveric liver transplantation, correlates with poor early graft function, rejection episodes, and contributes to donor organ shortage. Sirtuin 1 (SIRT1) is a histone deacetylase which may regulate inflammatory cell activity and manage liver function in IRI, though its functional role and clinical relevance remains to be elucidated. We investigated the efficacy of SIRT1 activation in murine liver IRI model and verified the concept of putative SIRT1-mediated hepatoprotection in clinical liver transplantation. In the experimental arm, mice were subjected to 90min of liver partial warm ischemia followed by 6h of reperfusion with or without adjunctive SIRT1 activation in vivo (Resveratrol, Res). In parallel, bone marrow-derived macrophage (BMDM) or spleen lymphocyte cultures were treated with Res. In the clinical arm, liver biopsies from twenty-one adult primary liver transplant patients (2h post-reperfusion) were divided into "low" (n=11) vs. "high" (n=10) SIRT1 expression groups, assessed by Western blots. Treatment with Res attenuated murine liver IRI while upregulating SIRT1, suppressing leukocyte infiltration and decreasing pro-inflammatory cytokine programs. SIRT1 silencing (siRNA) in BMDM cultures enhanced inflammatory cytokine program whereas addition of Res decreased proinflammatory response in SIRT1-dependent manner. In addition, Res decreased IFNγ production in liver-infiltrating and spleen lymphocyte cultures. Human liver transplants with high-SIRT1 levels showed improved hepatocellular function and superior survival (p=0.04), accompanied by lower pro-inflammatory cytokine profile. In conclusion, our translational study is the first to identify SIRT1 as a regulator of hepatocellular function in human liver transplant recipients under IR-stress. By targeting innate and adaptive immune activation, manipulation of SIRT1 signaling should be considered as novel means to combat inflammation in liver transplantation. This article is protected by copyright. All rights reserved.
