固有免疫细胞在肝脏损伤和再生中的效应机制
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摘要
肝脏是机体最大的消化器官，承担着分泌胆汁、合成涉及生命活动中重要蛋白质和解毒功能。与其它器官不同，肝脏具有肝动脉和门静脉两套血液供应途径，鉴于这种特殊的解剖学位置和功能，肝脏一直暴露于大量的肠道来源的抗原物质，包括病原菌、毒素、肿瘤细胞和细菌代谢产物以及无害的食物抗原，这样就决定了肝脏不仅承担着“内部血液过滤”的作用，同时还“肩负”清除肠道来源的外来物质的重任。所以人们推测肝脏必须拥有一套快速选择性的反应机制去应对这些肝脏特异性潜在“危险信号”。固有免疫反应作为入侵病原菌的一线防御机制，以及局部免疫反应机制在应对各种各样的免疫挑战中的作用备受青睐。已知肝脏是细胞因子、补体和急性期反应蛋白这类可溶性分子的合成部位，而且还有大量的吞噬细胞、抗原提呈细胞以及淋巴细胞。根据肝脏高比例的固有免疫细胞(主要指Kupffer细胞、NKT细胞和NK细胞)和它们对肝脏外源刺激的快速反应能力，肝脏被定义为具有固有免疫特性的器官已经被多家研究结果所支持，因此，通过结合“肝脏学”和“免疫学”，一门新型学科“肝脏免疫学”应运而生。大量资料研究显示肝脏积聚的这些固有免疫细胞在肝脏的免疫监视功能中发挥重要作用，譬如抗病毒、抗寄生虫和抗细菌感染。然而过度的免疫细胞活化有时可能对肝细胞进行意想不到的自身攻击，引起自身免疫性的肝脏损伤。本研究旨在探索固有免疫反应在肝脏免疫损伤和肝脏再生中的作用，主要试图回答以下三个科学问题：建立新型NK细胞介导的小鼠肝炎模型，推动NK细胞在自身免疫性肝病中作用机制的深入研究；深入了解NK细胞在ConA诱导的肝脏损伤的作用；肝脏固有免疫细胞对肝脏再生的调节机制，特别是探讨HBV感染是如何通过固有免疫反应途径来负调节小鼠肝脏再生。本研究获得的主要结果大致分为以下四个部分：
新型NK细胞介导、TLR3激动剂诱导的肝炎模型的建立：目前，T细胞、NKT细胞和巨噬细胞在自身免疫性肝炎中的作用研究甚多，相应的动物模型均有报道。然而，NK细胞在肝脏损伤中的作用似乎显得很神秘。本部分研究目的就是建立一种NK细胞介导的肝炎小鼠动物模型，来促进NK细胞在自身免疫性肝炎的机制研究。我们采用了TLR3配体聚肌胞(poly(I:C))活化NK细胞，观察后续的肝脏损伤。B6小鼠腹腔注射poly(I:C)20微克／克体重，通过流式细胞术分析肝脏NK细胞比例和绝对数，血清转氨酶和H&E染色被用作评价肝脏损伤的指标。发现poly(I:C)注射后，肝脏NK细胞显著
The liver is one of largest digestive organs in the body and carries on the functions in secretion of bile, synthesis of vital proteins and detoxification. Distinct with other organs, liver has a special double blood supply, liver artery and portal vein. In view of such special anatomical location and function, the liver is continuously exposed in the large load of the intestinal antigen that includes pathogens, toxins, tumor cells and harmless dietary antigens, making the liver not only bear "internal depurating blood" function, but also remove the foreign matter of intestinal source. It is speculated that these characteristics provide with the possibility that liver is endowed with a unique fast alternative immune response mechanism in response to the liver-specific potential danger signals. It is now being appreciated that innate immune response serves as the first line of defense against invading pathogens and the local immune mechanisms are required to cope with these diverse immunological challenges. It has been known that the liver is a site for the production of cytokines, complement components and acute phase proteins and contains large numbers of phagocytes, antigen-presenting cells and lymphocytes. According to the high proportion of innate immune cells and rapid responses to the stimuli in the liver, it is supposed that liver is a lymphoid organ with innate immune features, responding rapidly and functioning nonspecifically and with no memory. Therefore, a new subspecialty through combination of hepatology with immunology termed "hepatoimmunology" has emerged. Many studies have revealed that these innate immune cells abundant in the liver play a critical role in the immunosurveillance, such as protection from infection with bacteria, parasite, and virus. Meanwhile, some unexpected auto-attacks against hepatocytes mediated by over-activated innate immune cells in the live have often been found on some occasions. Our theme is to explore the roles of hepatic innate immune cells in the immune-mediated liver injury and repair, and mainly try to give answers to the following scientific questions: to establish a novel NK cell-mediated murine hepatitis model to facilitate the investigation of the NK cell role in autoimmune liver diseases; to further explore the dispensable role of NK cell in Concanavalin A-induced hepatitis; and to investigate the negative regulation of liver regeneration by hepatic innate
新型NK细胞介导、TLR3激动剂诱导的肝炎模型的建立：目前，T细胞、NKT细胞和巨噬细胞在自身免疫性肝炎中的作用研究甚多，相应的动物模型均有报道。然而，NK细胞在肝脏损伤中的作用似乎显得很神秘。本部分研究目的就是建立一种NK细胞介导的肝炎小鼠动物模型，来促进NK细胞在自身免疫性肝炎的机制研究。我们采用了TLR3配体聚肌胞(poly(I:C))活化NK细胞，观察后续的肝脏损伤。B6小鼠腹腔注射poly(I:C)20微克／克体重，通过流式细胞术分析肝脏NK细胞比例和绝对数，血清转氨酶和H&E染色被用作评价肝脏损伤的指标。发现poly(I:C)注射后，肝脏NK细胞显著
The liver is one of largest digestive organs in the body and carries on the functions in secretion of bile, synthesis of vital proteins and detoxification. Distinct with other organs, liver has a special double blood supply, liver artery and portal vein. In view of such special anatomical location and function, the liver is continuously exposed in the large load of the intestinal antigen that includes pathogens, toxins, tumor cells and harmless dietary antigens, making the liver not only bear "internal depurating blood" function, but also remove the foreign matter of intestinal source. It is speculated that these characteristics provide with the possibility that liver is endowed with a unique fast alternative immune response mechanism in response to the liver-specific potential danger signals. It is now being appreciated that innate immune response serves as the first line of defense against invading pathogens and the local immune mechanisms are required to cope with these diverse immunological challenges. It has been known that the liver is a site for the production of cytokines, complement components and acute phase proteins and contains large numbers of phagocytes, antigen-presenting cells and lymphocytes. According to the high proportion of innate immune cells and rapid responses to the stimuli in the liver, it is supposed that liver is a lymphoid organ with innate immune features, responding rapidly and functioning nonspecifically and with no memory. Therefore, a new subspecialty through combination of hepatology with immunology termed "hepatoimmunology" has emerged. Many studies have revealed that these innate immune cells abundant in the liver play a critical role in the immunosurveillance, such as protection from infection with bacteria, parasite, and virus. Meanwhile, some unexpected auto-attacks against hepatocytes mediated by over-activated innate immune cells in the live have often been found on some occasions. Our theme is to explore the roles of hepatic innate immune cells in the immune-mediated liver injury and repair, and mainly try to give answers to the following scientific questions: to establish a novel NK cell-mediated murine hepatitis model to facilitate the investigation of the NK cell role in autoimmune liver diseases; to further explore the dispensable role of NK cell in Concanavalin A-induced hepatitis; and to investigate the negative regulation of liver regeneration by hepatic innate
引文
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