Although pre-clinical studies have reported the efficacy of Sirtuin 1 (SIRT1) to protect livers from ischemia-reperfusion injury, its clinical relevance in liver transplantation (LT) has not been defined. In addition, cell-specific SIRT1 function and underling mechanisms to regulate innate immune response remains to be elucidated. Ikaros, a tumor suppressor of lymphoid lineage, is expressed in all hematopoietic cells, while its role in macrophage is unknown. We aimed to determine the clinical relevance of SIRT1 as well as to identify the significance of novel macrophage SIRT1-Ikaros axis in LT. Liver biopsies were collected at 2h post-reperfusion from 60 human adult primary LT recipients recruited under IRB protocol. SIRT1 levels were analyzed by Western blots and patients were divided into low-SIRT1 (n=30) and high-SIRT1 (n=30) groups. The high-SIRT1 group had depressed cleaved caspase-3 (0.54±0.06 vs. 1.00±0.14, p<0.05); lower sALT (238±28 vs. 488±65 IU/L, p<0.05) and sAST (281±41 vs. 766±325 IU/L) at POD1; and superior post-LT survival (2-year, 94.9% vs. 83.7%) with median follow-up of 940 days. Next, to determine the cell-specific SIRT1 function, groups of myeloid-specific SIRT1 (mSIRT1) knockout and WT mice (n=7-9/gr) were subjected to partial hepatic warm ischemia (90min) followed by reperfusion (6h). mSIRT1 deficiency exacerbated hepatocellular damage, evidenced by sALT/AST levels, Suzuki's histological grading and frequency of TUNEL+ cells (p<0.05). mSIRT1 disruption decreased Ikaros while increasing p-IκBα, cleaved caspase-3 (Western blot); enhanced mRNA levels of MCP1, CXCL10, TNFα while suppressing Arg1, Ym1; increased CD11b+ and Ly6G+ cell infiltration (p<0.05). Consistent with in vivo data, SIRT1 deficiency in bone marrow-derived macrophage (BMM) cultures decreased Ikaros, Arg1, Ym1, IRF4 while enhancing p-IκBα, p-Stat1, MCP1. Ikaros silencing by siRNA in BMM suppressed Arg1, Ym1, IRF4 but increased p-IκBα, p-Stat1, MCP1, indicating Ikaros functions downstream of SIRT1 to regulate macrophage M2 polarization. Conclusions: This study documents SIRT1-mediated hepatoprotection in LT patients and highlights critical role of macrophage SIRT1-Ikaros axis to regulate M2 differentiation and manage graft function, with implications for novel therapeutic strategies in transplant recipients.

CITATION INFORMATION: Nakamura K., Kageyama S., Li X., Aziz A., Sosa R., Reed E., Kaldas F., Busuttil R., Kupiec-Weglinski J. SIRT1-Ikaros Axis Promotes Macrophage M2 Polarization and Protects Liver Graft from Ischemia-Reperfusion Injury Am J Transplant. 2017;17 (suppl 3).

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