PD-1/PD-L1 抑制促进了扩大肝切除术后小体积肝中的肝再生。
PD-1/PD-L1 inhibition promotes hepatic regeneration in small-for-size liver following extended hepatectomy.
机构信息
Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China.
Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
出版信息
Cytokine. 2022 Nov;159:156017. doi: 10.1016/j.cyto.2022.156017. Epub 2022 Aug 30.
BACKGROUND
Small-for-size syndrome following liver surgery is characterized by compromised liver regeneration. Liver macrophages play key roles in initiating liver regeneration, and modulation of the immune microenvironment through macrophages may accelerate liver regeneration. In our current study, we aimed to explore the involvement of innate immunity after extended hepatectomy in rats and humans, and to test the effect of immunity modulation on small-for-size liver regeneration in rats.
METHODS
Serum programmed cell death protein ligand 1 (PD-L1) was measured after major hepatectomy and minor hepatectomy in humans and rats. Liver regeneration in rats was assessed using liver-to-body weight ratio and kinetic growth rate, antigen Ki67 and proliferating cell nuclear antigen (PCNA), and macrophage polarization was assessed by inducible nitric oxide synthase (iNOS), cluster of differentiation protein 163 (CD163) expression by immunohistochemistry (IHC) and iNOS/CD163 ratio. Rat hepatocyte BRL or human hepatocyte LO2 were co-cultured with rat bone marrow-derived macrophages or human macrophages THP-1. BMS-1 or Nivolumab were used to block programmed cell death protein 1 (PD-1)/PD-L1 in vitro and in vivo.
RESULTS
PD-L1 expressions were significantly higher following major hepatectomy compared to minor resection in both humans and rats; compromised liver regeneration after extended hepatectomy in rats was associated with PD-L1 upregulation and M2 macrophage polarization. M1 macrophages increased proliferation of hepatocytes through interleukin-6 (IL-6), and M2 macrophages decreased hepatocyte proliferation; blocking PD-1/PD-L1 reversed the effect of M2 macrophages on the survival of hepatocytes in vitro and promoted liver growth in rats through M1 macrophage polarization.
CONCLUSION
Compromised hepatic regeneration following extended hepatectomy is characterized by M2 macrophage polarization and upregulated PD-L1 expression. Blocking PD-1/PD-L1 may enhance small-for-size liver regeneration by inducing M1 macrophage polarization.
背景
肝手术后小肝综合征的特征是肝再生受损。肝巨噬细胞在启动肝再生中起关键作用，通过巨噬细胞调节免疫微环境可能加速肝再生。在本研究中，我们旨在探讨大鼠和人类肝切除术扩展后固有免疫的参与，并测试免疫调节对大鼠小肝综合征肝再生的影响。
方法
测量人类和大鼠肝大部切除和肝部分切除后血清程序性死亡蛋白配体 1（PD-L1）的变化。通过肝体比和动力学生长率、Ki67 和增殖细胞核抗原（PCNA）抗原、诱导型一氧化氮合酶（iNOS）、CD163 表达的免疫组化（IHC）和 iNOS/CD163 比值评估大鼠肝再生。大鼠肝细胞 BRL 或人肝细胞 LO2 与大鼠骨髓来源巨噬细胞或人巨噬细胞 THP-1 共培养。BMS-1 或 Nivolumab 用于体外和体内阻断程序性死亡蛋白 1（PD-1）/PD-L1。
结果
与肝部分切除相比，人类和大鼠肝大部切除后 PD-L1 表达显著升高；大鼠肝切除术扩展后肝再生受损与 PD-L1 上调和 M2 巨噬细胞极化有关。M1 巨噬细胞通过白细胞介素 6（IL-6）增加肝细胞增殖，M2 巨噬细胞减少肝细胞增殖；阻断 PD-1/PD-L1 可逆转 M2 巨噬细胞对体外肝细胞存活的影响，并通过 M1 巨噬细胞极化促进大鼠肝生长。
结论
肝切除术扩展后肝再生受损的特征是 M2 巨噬细胞极化和 PD-L1 表达上调。阻断 PD-1/PD-L1 可能通过诱导 M1 巨噬细胞极化增强小肝综合征肝再生。
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