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P-3.11 Small-for-size syndrome is characterized with PD-L1 upregulation in macrophage and blocking PD-L1 accelerates liver regeneration

Abstract

Small-for-size syndrome is characterized with PD-L1 upregulation in macrophage and blocking PD-L1 accelerates liver regeneration

Ji-Hua Shi1, Xin Yan1, Nuo Cheng1, Wen-Zhi Guo1, Shui-Jun Zhang1.

1Department of Hepatolgiliary & Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China

Background and Purpose: Small-for-size syndrome following partial hepatectomy and living donor liver transplantation is characterized with compromised liver regeneration. Liver macrophage accounts for priming liver regeneration through release of interleukin-6 (IL-6), and mediating immunosuppression through programmed cell death protein ligand 1 (PD-L1). Breakdown of intrahepatic immune microenvironment through modulation of PD-L1 may accelerate liver regeneration. The current study was to explore the innate immunity of small-for-size liver remnant after extended hepatectomy, and to investigate the effect of blocking PD-L1 on hepatocyte proliferation in vitro and in vivo.
Methods: Liver samples were obtained from rats following extended partial hepatectomy for RNA-sequencing, RT-PCR, and IHC. After major hepatectomy and minor hepatectomy in humans and rats, serum PD-L1 was detected. Liver regeneration in rats was evaluated with liver-to-body weight (LBW) ratio and kinetic growth rate (KGR), Ki67 and PCNA, and macrophage polarization was accessed by iNOS and CD163 expression by WB and IHC. BRL or LO2 hepatocytes co-cultured with rat bone marrow derived macrophages (BMDMs) or human THP-1 macrophages were compared with cell survival by CCK-8. PD-1/PD-L1 inhibitor, BMS-1 and Nivolumab, were employed to test the effect of blocking PD-L1 on proliferation of hepatocytes cocultured with M2 macrophages and the regeneration parameters after 80% PH in rats.
Results: Liver/serum PD-L1 levels were significantly higher after major hepatectomy in both humans and rats by RNA-sequencing, RT-PCR, and IHC (P<0.05); compromised liver regeneration after extended hepatectomy in rats was associated with intrahepatic and serum PD-L1 upregulation and M2 macrophage polarization (P<0.05). blocking PD-L1 reversed the effect of M2 macrophages on in vitro hepatocytes survival, and promoted liver growth in rats through M1 macrophage polarization (P<0.05).
Conclusion: Comprised hepatic regeneration following extended hepatectomy is characterized upregulated PD-L1 and blocking PD-L1 promotes small-for-size liver restoration.

References:

[1] Zhong Z, Schwabe RF, Kai Y, et al.Liver regeneration is suppressed in small-for-size liver grafts after transplantation: involvement of c-Jun N-terminal kinase, cyclin D1, and defective energy supply. Transplantation. 2006; 82: 241-50.
[2] Serenari M, Cescon M, Cucchetti A, Pinna AD. Liver function impairment in liver transplantation and after extended hepatectomy. World J Gastroenterol. 2013; 19: 7922-9. [4] Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Pathol. 2006; 30: 986-93.
[3] Shi JH, Line PD. Hallmarks of postoperative liver regeneration: An updated insight on the regulatory mechanisms. J Gastroenterol Hepatol. 2019; 29: 14944.

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