修回日期: 2015-03-30
接受日期: 2015-04-02
在线出版日期: 2015-05-28
Kupffer细胞(Kupffer cells, KCs)是体内最大的组织巨噬细胞群, 是肝脏固有免疫的重要功能细胞, 其在肝血窦中, 最早接触循环病原体. KCs在病毒性肝炎患者肝脏中数量明显增高, 提示其在相关免疫中起到重要作用. KCs不仅能够吞噬病毒颗粒清除病原体, 还能够提呈抗原、分泌细胞因子等, 参与多种炎症反应、免疫耐受以及对肝细胞的损害反应. 乙型肝炎病毒(hepatitis B virus, HBV)/丙型肝炎病毒(hepatitis C virus, HCV)感染中KCs相关的细胞因子的多样性、受体信号通路互相作用的复杂性以及细胞毒性作用的双重性等, 决定KCs在免疫反应中扮演着双重角色, 调节着病毒感染性肝炎中炎症和抗炎的平衡.
核心提示: Kupffer细胞(Kupffer cells)调节乙型肝炎病毒(hepatitis B virus, HBV)/丙型肝炎病毒(hepatitis C virus)感染时炎症和抗炎的平衡. 白介素-1β是关键炎症因子, 其产生依赖于NOD样受体家族pyrin域3(NOD-like receptor family pyrin domain containing 3, NLRP3)炎性小体激活; HBV通过Rac1通路激活NLRP3炎性小体, TIM-4抑制其活化. 探索调控NLRP3炎性小体的激活机制将有助于治疗病毒感染引起的肝损伤以及纤维化.
引文著录: 罗玉政, 李铁军. Kupffer细胞在乙型/丙型病毒性肝炎中的作用. 世界华人消化杂志 2015; 23(15): 2397-2403
Revised: March 30, 2015
Accepted: April 2, 2015
Published online: May 28, 2015
Kupffer cells (KCs) are the largest group of tissue macrophages. KCs in the hepatic sinusoid contact with pathogens from circulation earliest. The quantity of KCs increases significantly in patients with viral hepatitis, suggesting that KCs play an important role in viral hepatitis related immunity. KCs can not only engulf virus particles, but also present antigens, secrete cytokines, and participate in a variety of inflammatory responses, immune tolerance and liver injury. In hepatitis B virus (HBV)/hepatitis C virus (HCV) infections, the diversity of KCs-related cytokines, the complexity of interactions of receptor signaling pathways as well as the duality of cytotoxic effect, indicate that KCs play a dual role in the immune response; the activation of KCs regulates the balance of inflammatory and anti-inflammatory mechanisms in viral hepatitis.
- Citation: Luo YZ, Li TJ. Role of Kupffer cells in hepatitis B/C viral hepatitis. Shijie Huaren Xiaohua Zazhi 2015; 23(15): 2397-2403
- URL: https://www.wjgnet.com/1009-3079/full/v23/i15/2397.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i15.2397
Kupffer细胞(Kupffer cells, KCs)是体内最大的组织巨噬细胞群, 是肝脏固有免疫系统的重要功能细胞[1,2]. KCs位于肝血窦内, 最早接触循环中的病原体, 在肝细胞被感染之前就被激活[3,4]. 目前, 关于KCs在病毒性肝炎中作用的研究主要局限于乙型肝炎病毒(hepatitis B virus, HBV)和丙型肝炎病毒(hepatitis C virus, HCV)感染. 在HBV和HCV慢性感染患者肝脏中, KCs数量明显高于健康人, 且主要集中于汇管区; 其中, 免疫活跃期患者肝脏KCs较免疫抑制期的多, 并以炎症和坏死病灶周围为多[5,6]. 这提示KCs在病毒慢性感染的相关免疫中起到重要作用. KCs不仅能够吞噬病毒颗粒清除病原体, 还能够提呈抗原、分泌细胞因子等, 参与多种炎症反应、免疫耐受以及对肝细胞的损害反应, 在免疫反应中扮演着双重角色[7,8]. 本文将对KCs在HBV/HCV病毒感染性肝炎中的作用以及相关分子机制作一综述.
KCs位于肝血窦内, 最早接触循环中的病原体, 在肝细胞被感染之前就被激活. 肝炎病毒表面抗原复杂的蛋白结构有利于被KCs识别和吞噬, 摄取病毒后的KCs即可启动一系列效应清除病毒或抑制其复制. KCs主要通过细胞表面的结构识别受体来识别病毒抗原, 如Toll样受体(Toll-like receptors, TLRs)、CD14依赖受体、甘露糖受体、硫酸乙酰肝素糖蛋白(heparan sulfate proteoglycan, HSPG)以及树突状细胞特异性细胞黏附分子-3-结合非整合素分子(dendritic cells-specific intercellular adhesion molecule-3-grabbing nonintegrin, DC-SIGN)等[9,10]. 其中TLRs在早期HBV感染的宿主的防御过程中起着重要作用[11].
虽然尚未发现TLR有直接的抗病毒作用, 但研究[6,12]表明TLR2、TLR3、TLR4的激活均可使KCs产生抗病毒因子并参与机体抗病毒免疫[13,14]. CD14+ KCs和单核细胞分化的巨噬细胞可通过TLR2识别HCV核心和NS3, 并产生促炎因子白介素1β(interleukin 1β, IL-1β)、IL-6、干扰素β(interferon β, IFN-β)以及肿瘤坏死因子(tumor necrosis factor, TNF), 抑制HCV病毒复制[15]. TLR3通过与其配体结合后激活KCs, 产生IFN-β, 发挥抗病毒效应. KCs还可通过TLR4识别NS3, 并将信号传导入胞内, 激活核因子κB(nuclear factor kappa B, NF-κB)并促进肿瘤坏死因子α(tumor necrosis factor α, TNF-α)的释放[16,17]. Hösel等[18]指出HBV颗粒和乙型肝炎病毒表面抗原(hepatitis B surface antigen, HBsAg)通过激活NF-κB诱导KCs产生IL-1β、IL-6, 趋化因子8(CXC chemokine ligand 8, CXCL8)和TNF, 随后HBV在肝细胞中的复制被IL-6和TNF所抑制, 其中TNF主要通过非细胞损伤的形式抑制HBV复制.
KCs除了直接识别病毒抗原并释放细胞因子外, 还可以在肝脏中募集和激活其他免疫细胞, 间接影响免疫反应, 这使肝脏实质细胞、定植免疫细胞和浸润细胞间的互相作用更为复杂[19]. KCs产生的CXCL8在感染早期吸引NK细胞和NKT细胞, 并将之激活, 激活后的上述两种细胞产生细胞因子TNF、IFN-γ等以及发挥细胞毒性作用, 直接杀伤受感染的肝细胞, 间接抑制病毒的复制[18]. KCs通过C型凝集素将树突状细胞募集到肝脏, 增强其抗原提呈能力, 并促进病毒特异性的T细胞反应. 小鼠的KCs可直接将抗原呈递给CD4+和CD8+ T细胞, 诱导这些细胞的增殖并产生IFN-γ[20]. 在慢性乙型肝炎患者肝组织内发现高表达CD40、CD80和主要组织相容性复合体Ⅱ(major histocompatibility complex Ⅱ, MHC Ⅱ)分子标记的巨噬细胞提示KCs在抗原提呈方面可能发挥重要作用.
目前, 关于KCs在体内和体外与HBV和HCV直接相互作用的机制还不完全清楚. 巨噬细胞能够在体外和HBV及HCV病毒相关蛋白结合, 激活细胞表面受体或者胞内受体[21,22]. 然而, 这些受体激活后发挥的作用还需要进一步研究. 有研究报道, KCs通过抑制病毒复制来控制HBV和HCV的感染, 但是其发挥作用的方式既不是通过产生细胞因子来诱导病毒特异性的炎症反应, 也不是通过与其他细胞相互作用来达到抗病毒效应. 因此, 需要更进一步研究来阐释KCs在调节肝内免疫中的作用及相关分子基础.
一方面, KCs通过分泌细胞因子、与其他免疫细胞相互作用来清除病毒或抑制其复制; 另一方面, 病毒可以反过来影响KCs的免疫状态, 逃避其对自身的清除和杀伤作用[23,24]. 目前的研究显示, HBV/HCV病毒逃避机体免疫的主要机制有: (1)干扰KCs细胞内TLRs信号通路的激活, 减少抗病毒细胞因子的产生和释放, 增加免疫耐受细胞因子的分泌[25]; (2)诱导KCs高表达程序性死亡蛋白配体1(programmed death ligand-1, PD-L1)、人凋亡相关因子配体(Fas-ligand, FasL)、吲哚胺2,3-二氧化酶(indoleamine-2,3-dioxygenase, IDO)等配体分子, 促进T淋巴细胞调亡[26,27].
研究[28]发现, 乙型肝炎e抗原(hepatitis B e antigen, HBeAg)阳性的HBV感染患者体内KCs和外周血单核细胞(peripheral blood monouclear cells, PBMC)表达的TLR2较HBeAg阴性的患者和健康人低, 这可能与HBeAg抑制TLR2通路有关. 另外, 将人的单核细胞与HBeAg或HBsAg孵育, 可以抑制TLR2介导的p38和JNK-MAPK磷酸化以及IL-6、TNF和IL-12的产生. 用HBV处理KCs后, HBsAg、HBeAg以及病毒颗粒几乎可以完全抑制其TLR介导的抗病毒活性, IFN-β、人干扰素调节因子3(interferon regulatory factor 3, IRF3)、NF-κB和胞外信号调节激酶1/2(extracellular regulated kinase 1/2, ERK1/2)的表达显著减少. HBV患者KCs表达的TLR3也较健康人低, 而用恩替卡韦或IFN进行抗病毒治疗可回复TLR3的表达, 但具体机制不清[29]. HBV/HCV病毒不但可以减少抗病毒细胞因子的产生, 而且还增加免疫耐受因子的分泌, 形成肝内的耐受环境[30,31]. 研究[32,33]发现, 与健康人群相比较, 慢性HBV/HCV患者血清IL-10水平显著增高; HCV和HBV核心蛋白可诱导KCs产生IL-10, 进而抑制肝细胞产生抗病毒因子; 持续炎症状态下, KCs可激活活性被抑制的Treg细胞, 两者的互相作用促进IL-10的产生; IL-10可下调MHC Ⅱ和共刺激分子, 抑制KCs-NK细胞间作用, 削减其抗原呈递功能[34,35]. 在感染HBV的小鼠模型中, KCs和IL-10与外周HBsAg疫苗建立的抗原特异型免疫耐受有关[36]. 此外, HBV使小鼠KCs产生转化生长因子β(transforming growth factor β, TGF-β)增多, 而其主要作用是维持细胞对自身抗原的免疫耐受[37].
程序性死亡-1分子(programmed death, PD-1)是免疫系统的一种负性调节分子, 主要表达于激活的T细胞, 其配体分子有两种即PD-L1和PD-L2. 在肝脏内, 窦状内皮细胞及KCs均表达PD-L1. 研究[31,38]显示, 慢性病毒性肝炎患者PD-L1、PD-L2和PD-1水平高于健康人, 且与肝脏炎症程度有关. 与急性感染患者相比, HBV慢性感染患者体内CD4+和CD8+ T细胞的免疫应答水平显著减弱, 其体内T淋巴细胞不仅数量大大减少, 而且功能上有很大程度的衰减. 进一步研究[38]发现, 功能衰竭的T淋巴细胞高表达PD-1, 注射PD-L1抗体后, T淋巴细胞无论是数量还是功能上都有明显改善, 抗病毒效应得到明显. 因此, KCs高表达PD-L1与T淋巴细胞PD-1结合, 抑制T细胞增殖、导致其功能衰竭以及抗病毒细胞因子产生减少, 是HBV感染逃过宿主免疫系统的监视并形成慢性感染而发展为免疫耐受的重要分子机制. 最近研究[39]发现, 半乳凝素9(galectin-9)可能与PD-L1有相似的作用, 在慢性HCV患者血清中其表达水平显著高于正常人群, 但其具体作用机制还不清楚, 值得进一步深入研究.
IDO是一种特异性地表达于巨噬细胞或树突状细胞的催化色氨酸分解代谢的限速酶, 可导致微环境中色氨酸耗竭, 使细胞处于一种"色氨酸饥饿"状态, 处于迅速分裂期的细胞或病原微生物尤为敏感. IDO不但"剥夺"病原微生物的色氨酸, 同时也"剥夺"T淋巴细胞的色氨酸, 导致T细胞凋亡. 因此, 在病毒感染方面IDO是一把双刃剑. 在HBV/HCV病毒感染急性期, 淋巴细胞聚集释放IFN-γ, 诱导IDO表达, 对病毒复制产生非特异性抑制作用; 但当HBV/HCV慢性感染或活跃复制时, IDO过度表达, 在色氨酸缺乏的条件下, 活化的T细胞停滞在G1中期, 且变得更易于凋亡, 其细胞活化受到抑制, 使机体对HBV感染产生免疫耐受[40].
Fas/FasL系统是介导细胞凋亡的重要途径之一, HBV感染可导致机体Fas/FasL系统的表达及分布异常, 从而出现细胞凋亡的异常, 最终致肝组织损害和感染慢性化. HBV病毒感染可诱导KCs细胞FasL表达增强, 一方面FasL与肝细胞表面Fas结合后, 导致大量被感染的肝细胞凋亡, 同时病毒被清除; 另一方面, 肝组织内淋巴细胞也要表达Fas, 与KCs的FasL结合后, 导致淋巴细胞大量凋亡, 抗病毒因子产生减少, 最终引起HBV的清除障碍, 造成外周免疫耐受[41].
KCs的激活是一把双刃剑, 一方面他们通过释放抗病毒因子清除病毒; 另一方面他们产生多种促炎因子对肝细胞造成损伤. 病毒性肝炎相关肝损伤主要包括肝细胞本身的损伤和肝纤维化. 急性期病毒感染引起的肝细胞损伤主要与KCs释放的细胞因子和促炎因子有关[42,43]. 近年研究[44]发现KCs产生的TNF的一个新作用, 他可以通过激活连接蛋白和增加HCV受体CD81增加肝癌细胞对HCV的通透性, 进而间接促进HCV感染. 另外, KCs可表达肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor related apoptosis-inducing ligand, TRAIL)、颗粒酶B、穿孔素和活性氧(reactive oxygen species, ROS)等细胞毒性分子, 促进感染肝细胞的溶解[45]. KCs一旦开始通过这种非特异性方式溶解肝细胞, 就不局限于感染了的肝细胞, 这样KCs的细胞毒性就对器官造成的更大的损伤. 慢性HBV感染的肝细胞损伤可能与KCs表达FasL增加有关, 其导致经Fas/FasL途径凋亡的肝细胞增加, 从而致肝组织损害. 传统观点认为, HBV和HCV主要通过激活肝星状细胞直接或者间接参与细胞损伤、调亡、坏死以及修复, 最终导致肝纤维化形成[46]. 但是最近研究[47]表明, KCs在肝纤维化中同样扮演了重要角色, 他们通过释放各种促纤维化因子诱导肝星状细胞的激活, 如ROS、IL-6、TNF、血小板源性生长因子(platelet derived growth factor, PDGF)以及TGF-β. 除此之外, KCs还产生多种酶类破坏细胞外基质, 如胶原酶以及金属蛋白酶, 同时调节其他细胞产生细胞因子, 导致细胞稳态的破坏和细胞外基质的沉积. 另外, 研究证实IL-1β是重要的促纤维化因子之一, 其在肝脏中的主要来源是KCs. KCs受HBV和HCV刺激后均可释放IL-1β和IL-18, 且免疫荧光发现慢性病毒性肝炎患者肝脏内IL-1β和CD68共表达, 同时血浆中的IL-1β也较健康人升高[12,48]. IL-1β的产生主要依赖于TLRs信号的激活, 而其成熟和释放依赖于NOD样受体家族pyrin域3(NOD-like receptor family pyrin domain containing 3, NLRP3)炎性小体的激活, 并需要Caspase1; HBV通过Ras相关性C3肉毒杆菌毒素底物(Ras-related C3 botulinum toxin substrate 1, Rac1)通路激活NLRP3炎性小体, T细胞免疫球蛋白功能区和黏蛋白功能区分子4(T-cell immunoglobulin-domain and mucin-domain-containing molecule-4, TIM-4)抑制NLRP3炎性小体的活化[49,50]. 因此, 如何调控NLRP3炎性小体的激活, 探索其内在的分子机制将有助于治疗病毒感染引起的肝损伤以及纤维化.
KCs作为肝脏固有免疫系统的重要组成部分, 在HBV/HCV急慢性感染中扮演着双重角色, 一方面其激活能有效地抑制HBV病毒复; 另一方面, 造成肝细胞损伤和纤维化. KCs调节着炎症和抗炎的平衡, 如何调控KCs细胞的免疫状态, 增强其正面效应而减少其负面效应将是未来研究的方向, 也将为病毒性肝炎的治疗提供新的思路.
Kupffer细胞(Kupffer cells, KCs)是机体最大的单核巨噬细胞群. 他位于肝血窦内, 最早接触循环病原体, 是炎症因子的主要来源, 主要介导固有免疫反应, 在病毒慢性感染的相关免疫以及肝脏损伤的过程中扮演重要角色.
张明辉, 教授, 主任医师, 河北省唐山市人民医院感染性疾病科
乙型肝炎病毒(hepatitis B virus, HBV)/丙型肝炎病毒(hepatitis C virus, HCV)可以被KCs清除, 也可影响KCs的免疫状态, 逃避自身被清除和杀伤, 其逃避机制主要有: (1)干扰KCs细胞内Toll样受体(Toll-like receptors)信号通路的激活, 减少抗病毒细胞因子的产生和释放, 增加免疫耐受细胞因子的分泌; (2)诱导KCs高表达程序性死亡蛋白配体1(programmed death ligand-1, PD-L1)、人凋亡相关因子配体(Fas-ligand)、吲哚胺2,3-二氧化酶(indoleamine-2,3- dioxygenase)等配体分子, 促进T淋巴细胞调亡.
Chen等发现功能衰竭的T淋巴细胞高表达PD-1, 注射PD-L1抗体后, T淋巴细胞数量、功能明显改善. KCs高表达PD-L1与T淋巴细胞PD-1结合, 抑制T细胞增殖、导致其功能衰竭, 是HBV免疫耐受的重要分子机制.
KCs在HBV/HCV急慢性感染中扮演着双重角色, 一方面其激活能有效地抑制HBV病毒复; 另一方面, 造成肝细胞损伤和纤维化. KCs调节着炎症和抗炎的平衡, 如何合理调控KCs细胞的免疫状态, 增强其正面效应而减少其负面效应将为病毒性肝炎的治疗提供新的思路.
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编辑:韦元涛 电编:都珍珍
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