修回日期: 2022-10-02
接受日期: 2022-10-20
在线出版日期: 2022-12-08
克罗恩病(Crohn's disease, CD)是一种慢性炎症性消化道疾病, 其发病涉及遗传、环境及菌群等多方面因素. 在遗传因素方面, 克罗恩病的许多易感基因和致病途径均与帕内特细胞(Paneth cell, PC)相关. 多项研究证明帕内特细胞在克罗恩病的发病中涉及了肠道微生物群、肠上皮屏障功能障碍和免疫异常等方面, 为克罗恩病的预防及潜在的治疗靶点提供了新思路. 本文综述了帕内特细胞相关的克罗恩病易感基因如何调控帕内特细胞从而导致克罗恩病的发生.
核心提要: 遗传易感性是影响克罗恩病(Crohn's disease, CD)发病的重要因素之一, 研究发现帕内特细胞(Paneth cell, PC)功能障碍与CD易感性显著相关, 从PC细胞先天性模式识别受体相关基因、自噬相关基因、PC分化相关基因、维持肠上皮屏障相关基因等方面阐明PC细胞在克罗恩病发病中的作用, 以期为临床研究提供参考.
引文著录: 爱丽斯, 于岩波. 帕内特细胞相关的克罗恩病易感基因在克罗恩病发生中的作用. 世界华人消化杂志 2022; 30(23): 1009-1015
Revised: October 2, 2022
Accepted: October 20, 2022
Published online: December 8, 2022
Crohn's disease (CD) is a chronic inflammatory digestive tract disease, and its pathogenesis involves many factors such as genetics, environment, and flora. In terms of genetic factors, many susceptibility genes and pathogenic pathways of CD are associated with Paneth cells (PCs). Numerous studies have demonstrated that PCs are involved in the pathogenesis of CD by affecting the gut microbiota and inducing intestinal epithelial barrier dysfunction and immune abnormalities. These advances provide new ideas for the prevention of CD and potential therapeutic targets for this disease. This article reviews the role of PCs-associated CD susceptibility genes in the pathogenesis of CD.
- Citation: Ai LS, Yu YB. Role of Paneth cells-associated Crohn's disease susceptibility genes in development of Crohn's disease. Shijie Huaren Xiaohua Zazhi 2022; 30(23): 1009-1015
- URL: https://www.wjgnet.com/1009-3079/full/v30/i23/1009.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i23.1009
克罗恩病(Crohn's disease, CD)是一种以典型的节段性和透壁性溃疡为特征性表现的、慢性炎症性消化道疾病, 和溃疡性结肠炎(ulcerative colitis, UC)同属于炎症性肠病(inflammatory bowel disease, IBD)[1]. 自1900年以来, CD在新兴工业化国家的发病率不断上升, 并给患者和社会带来负担[2], 因此需要我们更深入的探究CD可能的发病机制, 从而再认识疾病的预防及潜在的治疗新靶点. CD的病因尚不完全清楚, 目前普遍认为它是由遗传易感性、环境因素和肠道菌群相互作用导致异常的黏膜免疫反应和上皮屏障功能受损[3]. 研究表明[4], 肠上皮屏障有助于维持黏膜免疫稳态, 肠道免疫系统可以对共生菌群及食物抗原产生免疫耐受, 而对肠道病原体产生适度的免疫应答, 两者在正常情况下保持平衡. 然而由于肠黏膜稳态遭到破坏, 引起肠黏膜对共生非致病性细菌的异常免疫反应, 导致CD患者肠道防御能力减弱, 继而在其他因素的共同作用下引发了慢性炎症反应[5,6].
帕内特细胞(Paneth cell, PC)是一种在隐窝内自干细胞分化的小肠特化的上皮细胞[7], 有助于维持肠黏膜稳态[8], 它通过表达表皮生长因子、转化生长因子α等多种信号分子, 使位于小肠隐窝底部的G蛋白偶联受体5干细胞完成小肠隐窝的不断更新[9,10]. PC可以分泌包括抗菌肽(antimicrobial peptides, AMPs)在内的多种抗菌蛋白. 防御素是AMPs重要的蛋白质家族之一[11,12], PC主要表达两种α-防御素-人类防御素5(human α-defensin 5, HD5)和人类防御素6(human α-defensin 6, HD6). HD5可以调节肠道微生物群组成[13], HD6保护人类小肠免受多种肠道病原体入侵[14], PC功能障碍可能导致AMPs表达降低或活性受损, 从而对肠道内微生物产生不利影响[15,16]. 研究表明[17], CD防御素的相对缺乏, 使AMPs和腔内细菌之间的平衡被打破, 肠道微生物黏附并侵入黏膜引发炎症. PC功能障碍不仅阻碍小肠上皮细胞的更新, 而且无法抵御细菌在黏膜的附着和入侵[18,19], 在CD的发病过程中发挥关键作用. 综上所述, CD很可能是一种复杂的PC相关疾病[20].
PC整合肠道微生物群、肠上皮屏障功能障碍和免疫异常等因素参与CD的发病[9], 因此被认为可能是CD发病中的关键[20], 分子遗传学和流行病学研究表明, 约50%的CD起源于宿主的基因构成[21], 全基因组关联研究确定了163个与IBD相关的基因变异, 110个是CD和UC共同的变异位点, 另有30个是CD特异性基因变异位点[22], 其中有数个PC相关基因与CD易感性显著相关[23,24], 如核苷酸结合寡聚化结构域蛋白2 (nucleotide-binding oligomerization domain 2, NOD2)、自噬相关16样蛋白1(autophagy-related 16-like 1, ATG16L1)、免疫相关鸟苷三磷酸酶家族M(immunity-related GTPase family M, IRGM)、无翅相关集合位点(wingless-related integration site, Wnt)、富亮氨酸重复激酶2(leucine-rich repeat kinase 2, LRRK2)、组蛋白去乙酰化酶(histone deacetylases, HDACs)、半胱氨酸蛋白酶-8(caspase-8, Casp8) 、X盒结合蛋白1(X-box-binding protein-1, XBP1)等[25].
NOD2是第一个发现的与PC相关的CD易感基因[26,27]. 目前已知约80%的CD易感性与NOD2在R702W, G908R, 1007fs这3个位点的突变相关[28,29], 该基因通过识别细菌细胞壁中的壁基二肽分子(muramyl dipeptide, MDP)直接激活适应性免疫系统, 或通过α-防御素、免疫刺激分子、辅助受体等途径间接激活适应性免疫系统[30]. 另一方面, NOD2参与AMPs的分选:内质网合成的AMPs, 在高尔基体中形成专一的高密度核心囊泡(dense core vesicles, DCV)[31], 保留有AMPs的DCV从高尔基体中分泌后[32], NOD2首先将LRRK2招募到DCV表面, MDP强化NOD2的DCV定位, 继而招募受体相互作用蛋白2(receptor interacting protein 2, RIP2), LRRK2增强或稳定由共生细菌来源信号传导所触发的NOD2-RIP2复合体[33], 在DCV成熟过程中指导溶菌酶的分选[32]. 研究发现[34,35], 如果NOD2缺乏, AMPs将不再继续留存在DCV中从而影响溶菌酶分选, 使肠道抗菌能力下降. 已行回肠造瘘的活动期CD患者其回肠分泌物内HD5的含量低于健康对照组[36], 当存在NOD2突变时HD5表达下降更明显[37], 因此, NOD2基因突变可以导致肠黏膜免疫反应异常启动从而引发CD[36,37].
自噬在上皮细胞中起着重要的稳态作用, 包括避免宿主细胞损伤, 抑制炎症反应, 降解病原体[38,39]. 自噬相关的遗传变异可能导致病原体清除能力降低, 在其他因素的共同作用下引发炎症反应[40,41]. 因此, PC功能缺失可能是CD上皮细胞缺陷的基础[42].
ATG16L1基因是编码处理细胞内细菌自噬体途径中的一种蛋白质[43], ATG16L1T300A是目前已知的与CD易感性最显著的ATG16L1变异类型, 携带ATG16L1T300A突变基因的人群的CD患病率是正常人群的2倍[44]. ATG16L1和NOD2 通过同一途径发挥抗菌作用, NOD2招募ATG16L1到细菌入侵部位的质膜表面启动细菌自噬[45]. 研究发现ATG16L1 缺陷引起的自噬损伤会改变PC中的蛋白质组丰度谱[46], 使PC分泌抗菌蛋白功能受到抑制. 携带ATG16L1T300A基因的小鼠其沙门氏菌感染引起的结肠炎发生率增加[47]. 此外, ATG16L1对于防止PC细胞过度死亡至关重要, ATG16L1通过维持线粒体稳态来防止TNF-α介导的PC坏死性凋亡, 通过抑制上皮细胞的坏死来维持肠道屏障[48,49].
免疫相关的IRGM是一种在PC中介导炎症和自噬的蛋白质, 研究发现其对CD发挥保护作用[50]. IRGM基因可通过稳定细胞核心自噬调控因子、激活自噬、防止过度炎症、增强IRGM组装自噬核心机制等四种方式发挥其抗炎和抗微生物特性[41]. IRGM通过抑制核苷酸结合寡聚化结构域样受体蛋白3(nucleotide oligomerization domain-like receptor family pyrin domain containing 3, NLRP3)从而抑制促炎细胞因子(白细胞介素1β、白细胞介素18和肿瘤坏死因子/肿瘤坏死因子-α)的转录发挥抗炎作用[51], IRGM1基因敲除的小鼠暴露于葡聚糖硫酸钠(dextran sulfate sodium, DSS)后肠炎症状加剧, 即使不暴露于DSS溶液, IRGM1基因敲除的小鼠也存在明显的PC功能障碍[52]. McCarroll等[53]发现了一个常见的IRGM缺失多态性, 该多态性与CD的一个单核苷酸多态性(single nucleotide polymorphisms, SNP)相关, 他们还报道IRGM抑制了与CD相关的胞内细菌的自噬; Rufini等[54]报道IRGM多态性对CD的易感性和表型调节(纤维狭窄行为、回肠疾病、肛周疾病和肠切除)的重要性, 表明IRGM变异可能调节CD的临床特征.
LRRK2是一种具有多个可识别结构域的大型蛋白[55], 研究发现[56]LRRK2表达增加的小鼠表现出Dectin-1介导的细胞因子反应增加, 虽然LRRK2 转基因小鼠没有出现自发性肠炎, 但暴露于DSS溶液后, 这些小鼠的结肠炎发生率增加, 由此说明, LRRK2转基因小鼠在炎症刺激后表现出对肠道炎症的易感性. 此外LRRK2还具有抑制自噬等功能, LRRK2信号介导的自噬抑制导致LRRK2的增加, 从而可能导致炎症的增强, 此外, LRRK2介导的自噬抑制还具有促炎作用的可能[56], 这些研究说明, LRRK2的激活会引发先天免疫反应从而引发CD. 此外, LRRK2作用于RIP2定位到DCV的过程中, 通过NOD2-LRRK2-RIP2-Rab2a组成的遗传通路负责PC溶菌酶的分选, 与NOD2共同作用并指导PC的溶菌酶分选[33].
Wnt是保持肠上皮干细胞增殖状态的重要因子[57], 能够刺激PC的分化和成熟过程, 从而调节HD5和HD6的表达[58]. 经典的Wnt通路是通过PC释放Wnt配体与细胞表面受体结合而激活[59], 激活后的Wnt通路介导β-连环蛋白的稳定, 并使之转移到细胞核中结合转录因子TCF-4、TCF-1等[60], 并启动HD5、HD6等靶基因转录. 研究表明回肠CD患者的TCF-4、TCF-1的表达降低进而导致HD5和HD6的表达下降[61,62]. 回肠CD患者表现出较高频率的TCF-4基因变异(rs3814570, rs10885394, rs10885395)[63], 此外, 另一个在β-连环蛋白的细胞质稳定中起关键作用的Wnt因子-低密度脂蛋白受体相关蛋白6(low density lipoprotein receptor-related protein 6, LRP6), 也在CD中被修饰从而导致HD5表达减少, 18岁以下的回肠CD患者LRP6(rs2302685)突变率达10.63%[63]. CD患者单核细胞Wnt配体表达减少对HD5和HD6的分泌产生负面影响, 导致了细菌入侵和黏膜慢性炎症[15].
HDAC是一种调节转录、DNA复制和修复的酶, 共有10多种亚型, 其中HDAC1、HDAC2和HDAC3与PC和CD有关; 研究发现[64], HDAC1和HDAC2都是重要的肠上皮细胞稳态调节因子, 其缺失会改变Notch和mTOR信号通路, 从而导致慢性炎症和内稳态失衡[65,66]. 并表现出PC分化改变[65]. 肠上皮细胞特异性HDAC3基因敲除的小鼠(intestinal epithelial cell specific deletion of the epigenome-modifying enzyme histone deacetylase 3, HDAC3ΔIEC)表现出广泛的肠上皮细胞抗菌相关的基因表达下降[67], 且对肠道损伤和炎症的易感性显著增加, 表明HDAC3的表达在维持肠道稳态中起着重要作用, 另外将HDAC3ΔIEC小鼠置于无菌环境中, 发现肠道屏障功能在很大程度上得到了恢复, 这一结果说明了HDAC3是整合共生细菌信号的关键因子, 在维持肠道稳态方面发挥了重要作用[67].
Casp-8是一种半胱氨酸蛋白酶, 在调节细胞凋亡中起关键作用. 在肠道中, Casp-8介导的细胞凋亡对肠上皮细胞的更新和塑造肠道结构至关重要[68]. Casp-8通过抑制受体相互作用的丝苏氨酸激酶1(receptor-interacting serine-threonine kinase 1, RIPK1)和受体相互作用的丝苏氨酸激酶3(receptor-interacting serine-threonine kinase 3, RIPK3)抑制TNF-α诱导的坏死性凋亡, 以此在预防PC坏死性凋亡和末端回肠炎中起关键作用[69,70], 在鼠伤寒沙门氏菌感染过程中, Casp-8对于维持肠道屏障功能和阻止病原体定植至关重要[71], 研究发现Casp-8缺失与暴发性肠上皮坏死、严重PC凋亡、继发性肠炎相关[72]. 但目前为止Casp-8基因在CD中的作用尚未完全确定[73].
XBP1是核内体应激反应的关键转录因子, 在CD患者中发现了XBP1的基因变异[74]. 一方面, XBP1通过阻止细胞凋亡、介导细胞更新来调节PC水平[74]. 研究表明[75], 上皮细胞特异性XBP1基因缺失的小鼠表现PC功能显著受损从而导致了AMPs的分泌不足, 使肠道对致病菌的防御能力下降, 另一方面, XBP1通过影响内质网应激途径影响了PC的发育, 内质网应激可增强肠上皮细胞中促炎JNK/SAPK信号通路[76]. 因此, XBP1在CD的发病中整合了肠道菌群和黏膜免疫系统因素, 并且两种机制共同作用, 互相促进, 进而导致肠炎的发生.
帕内特细胞具有多种功能, 它对黏膜发育、宿主防御和微生物群调节的贡献是维持肠道稳态的关键. PC维持肠道稳态的研究主要集中在其产生的抗菌肽以及抗菌肽与肠黏膜表面微生物的动态相互作用上, PC分泌的抗菌肽可以调节肠道菌群组成, 肠道菌群中的特定细菌种类能够驱动宿主的免疫反应, 促进炎症的发生. 因此, 肠道黏膜表面细菌与抗菌肽等的互动能够维持肠道内环境的平衡. 由此, 很容易理解PC功能障碍与CD的易感性相关, 这种特化细胞的遗传缺陷导致抗菌肽缺陷可能是CD的致病关键, 这为CD的预防及治疗新靶点带来了全新的认识, 因此我们需要进一步重视PC在CD发生中的重要作用.
学科分类: 胃肠病学和肝病学
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