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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 Feb 28;48(2):252–259. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.220337

细胞焦亡在肠道炎性损伤中作用的研究进展

Research progress in effects of pyroptosis on intestinal inflammatory injury

LIU Dandan 1,2, ZHONG Xiaolin 1, CAO Wenyu 2, CHEN Ling 1,✉
Editor: 郭 征
PMCID: PMC10930348  PMID: 36999472

Abstract

Inflammatory injury of the intestine is often accompanied by symptoms such as damage to intestinal mucosa, increased intestinal permeability, and intestinal motility dysfunction. Inflammatory factors spread throughout the body via blood circulation, and can cause multi-organ failure. Pyroptosis is a newly discovered way of programmed cell death, which is mainly characterized by the formation of plasma membrane vesicles, cell swelling until the rupture of the cell membrane, and the release of cell contents, thereby activating a drastic inflammatory response and expanding the inflammatory response cascade. Pyroptosis is widely involved in the occurrence of diseases, and the underlying mechanisms for inflammation are still a hot spot of current research. The caspase-1 mediated canonical inflammasome pathway of pyroptosis and caspase-4/5/8/11-mediated non-canonical inflammasome pathway are closely related to the occurrence and development of intestinal inflammation. Therefore, investigation of the signaling pathways and molecular mechanisms of pyroptosis in intestinal injury in sepsis, inflammatory bowel diseases, infectious enteristic, and intestinal tumor is of great significance for the prevention and treatment of intestinal inflammatory injury.

Keywords: pyroptosis, intestinal inflammatory injury, inflammation, sepsis, inflammatory bowel diseases, infectious enteritis, intestinal tumor

肠道炎性损伤是脓毒症肠道损伤、炎性肠病(inflammatory bowel disease，IBD)、感染性肠炎以及肠道肿瘤等疾病中的常见病理现象。肠道是人体较大的免疫器官，含有丰富的微生物菌群。肠道细胞的死亡方式多样。细胞焦亡是近年新发现的一种细胞程序性死亡方式，机体通过诱导炎症因子的释放，启动细胞程序性死亡[1]。细胞焦亡与肠道炎性损伤之间的关系密切。不同途径的细胞焦亡发生在免疫细胞或肠黏膜上皮细胞，其意义是不同的。因此，探究细胞焦亡对肠道炎性损伤的作用，对研究肠道炎性损伤的机制和临床治疗具有重要意义。

1. 细胞焦亡

细胞焦亡是1992年首次观察到的形态上不同于细胞凋亡的一种细胞死亡形式[2]。2001年研究[3]提出，细胞焦亡是一种胱天蛋白酶(caspase)-1介导的细胞程序性死亡。之后，随着研究的深入，其概念得到了进一步完善。目前，细胞焦亡被定义为由病原微生物或非感染因素刺激引起的一种固有免疫反应，是细胞内依赖caspase-1/3/4/5/8/11驱动，炎症小体介导的一种程序性死亡[4]。细胞焦亡主要包括caspase-1依赖的经典途径以及caspase-4/5/11、caspase-3/8诱导的非经典途径。

1.1. 细胞焦亡的经典途径

细胞焦亡的经典途径依赖caspase-1的激活，其中炎症小体在caspase-1的激活中发挥至关重要的作用。目前，已被确定参与固有免疫的典型炎症小体有：核苷酸结合寡聚化结构域样受体蛋白(nucleotide-binding oligomerization domain-like receptor protein，NLRP)1、NLRP3、NLRP4和黑色素瘤缺乏因子2(absent in melanoma 2，AIM2)[5]。炎症小体作为细胞质内核苷酸结合寡聚化结构域样受体(nucleotide-binding oligomerization domain-like receptor，NLR)家族成员，具有特异性识别功能，可被Toll样受体4(Toll-like receptor 4，TLR4)、腺苷三磷酸(adenosine triphosphate，ATP)、低密度脂蛋白(low density lipoprotein，LDL)等多种因素激活[6]。NLRP3是介导焦亡的主要炎症小体，其激活需要跨膜蛋白TLR4、ATP依赖的受体这两个信号。激活后的NLRP3与胱天蛋白酶募集域(caspase recruitment domain，CARD)结构的凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing CARD，ASC)相互作用，募集前caspase-1(pro-caspase-1)并将其切割形成活化的caspase-1，激活下游信号分子，从而参与疾病发生和发展[7]。活化的caspase-1识别并剪切前体白介素(interleukin，IL)-18和前体IL-1β，促使其形成成熟的IL-18、IL-1β。由caspase-1剪切、活化gasdermin蛋白家族成员(gasdermin，GSDM)D的N端，被切割后形成的N端GSDMD可在磷脂膜上聚集形成细胞膜孔，促使IL-18、IL-1β等炎症因子通过细胞膜孔释放，启动过度免疫，最终导致细胞焦亡[8]。

1.2. Caspase-4/5/11诱导的细胞焦亡非经典途径

细胞内的脂多糖(lipopolysaccharide，LPS)也可通过活化caspase-4/5/11，介导细胞焦亡。活化后的caspase-4/5/11与caspase-1的作用类似，剪切、活化GSDMD导致细胞焦亡。相对于由caspase-1诱导的经典焦亡途径，这种诱导途径被称为细胞焦亡的非经典途径，细胞焦亡的概念得到进一步延伸[9-10]。革兰氏阴性菌以外膜囊泡的形式将细菌LPS递送到细胞膜上，细胞内吞并释放LPS，caspase-4/5/11与之直接结合后被激活，诱导焦亡[11]。活化的caspase-11可裂解GSDMD的N端结构域，N端一方面直接聚集在细胞膜上导致细胞膜破裂，引起细胞焦亡；另一方面通过激活炎症小体NLRP3以活化caspase-1，产生高迁移率族蛋白1(high mobility group box-1，HMGB1)及IL-1β、IL-18等炎症因子，引起炎症反应[12]。

1.3. Caspase-3/8诱导的细胞焦亡非经典途径

肿瘤坏死因子α(tumor necrosis factor α，TNF-α)或化学治疗药物可诱导caspase-3特异性切割GSDME，产生可穿透细胞膜的GSDME N端片段，从而使细胞凋亡转变为细胞焦亡[13-14]。当发生鼠疫耶尔森菌感染时，在炎症信号转导期间抑制转化生长因子-β激活激酶1(transforming growth factor-β-activated kinase 1，TAK1)的情况下，caspase-8的激活可活化小鼠巨噬细胞中的GSDMD和GSDME，从而诱导细胞焦亡[15]。近期研究[16]发现：在抑制TAK1时，Fas相关死亡结构域蛋白(Fas-associating via death domain，FADD)-受体相互作用蛋白激酶1(receptor interacting protein kinase 1，RIPK1)-caspase-8的复合物通过Rag-Ragulator复合物被招募到溶酶体膜，并在TLR和肿瘤坏死因子受体(tumor necrosis factor receptor，TNFR)连接时激活FADD-RIPK1-caspase-8，进而切割GSDMD，诱导细胞焦亡。细胞焦亡的经典途径及非经典途径见图1。

图1.

图1

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细胞焦亡的经典途径及非经典途径

Figure 1 Canonical and non-canonical pathway of pyroptosis LPS: Lipopolysaccharide; TLR4: Toll-like receptor 4; TNFR: Tumor necrosis factor receptor; ATP: Adenosine triphosphate; NLR: Nucleotide binding oligomerization domain-like receptor; LDL: Low density lipoprotein; ASC: Apoptosis-associated speck-like protein containing CARD; TNF-α: Tumor necrosis factor α; TAK1: Transforming growth factor β-activated kinase 1; RIPK1: Receptor-interacting protein kinase 1; FADD: Fas-associating via death domain; GSDM: Gasdermin; IL: Interleukin.

2. 细胞焦亡与肠道炎性损伤

2.1. 细胞焦亡与脓毒症肠道损伤

脓毒症是一种器官功能障碍综合征[17]，主要表现为寒战、发热、心慌、气促等症状[18-19]。脓毒症的发生和发展与肠道损伤关系密切。肠道是脓毒症患者最先出现功能障碍的器官之一，肠道损伤可促进脓毒症发展为脓毒症休克甚至多器官功能衰竭[20]。肠道功能紊乱是脓毒症病情加重的重要原因[21]，包括肠道免疫细胞程序性死亡显著增加和免疫功能受损、肠道微生态失衡、肠道黏膜细胞和屏障功能受损、肠道通透性和动力发生改变等。在脓毒症早期，免疫细胞程序性死亡是宿主启动的免疫防御反应之一。适度的细胞焦亡可以抵御病原微生物的感染，过度激活的细胞焦亡则可能加重脓毒症及脓毒症休克[22]。在脓毒症感染早期，宿主通过caspase-1经典途径介导细胞焦亡，释放炎症因子来抵御病原微生物的侵袭[23]。如沙门菌感染猪肠系膜淋巴结细胞诱导的细胞焦亡，裂解的caspase-1通过释放炎症因子激活宿主的免疫应答反应，从而维持肠道稳态[24]。查尔酮类似物lead 40可通过抑制活性氧的生成，有效阻断NLRP3炎症小体的激活，防止细胞焦亡的发生，并且其对脓毒症肠道损伤具有显著的治疗效果[25]。溴结构域蛋白4(bromodomain-containing protein 4，BRD4)在脓毒症肠道损伤相关细胞焦亡中起关键作用，其抑制剂JQ1可显著抑制结肠组织中核因子-κB(nuclear factor-κB，NF-κB)的磷酸化以及NLRP3/ASC/caspase-1炎症小体复合物的激活，对脓毒症肠道损伤具有重要的保护作用[26]。一氧化碳可以通过抑制caspase-1和caspase-11的裂解，使IL-18、IL-1β和HMGB1的表达水平降低，从而减少肠道黏膜上皮细胞焦亡的发生，有效降低肠黏膜的通透性，减轻肠黏膜的损伤[27]。HMGB1作为一种晚期炎症介质，参与脓毒症的发病过程[28]，是脓毒症晚期的重要促炎因子。伴随脓毒症的发生，组织中的HMGB1水平显著升高[29-30]。给予HMGB1的中和抗体对内毒素造成的肠道屏障功能损伤具有明显的保护作用[31-32]。由此可见，caspase-1介导的细胞焦亡经典途径在脓毒症肠道损伤中发挥着至关重要的作用。通过探究脓毒症肠道损伤中肠道免疫细胞或肠道上皮细胞焦亡的具体机制，可为疾病的临床防治提供新思路。

2.2. 细胞焦亡与IBD

NLRP3是维持肠道内环境稳定的重要炎症小体[33]。NLRP3缺失小鼠的结肠组织中细胞焦亡水平下调，并可明显抵抗IBD的发生[34]。IBD包含溃疡性结肠炎和克罗恩病两种独立的疾病。研究[35]发现：溃疡性结肠炎患者的产丁酸盐细菌Roseburia intestinalis(R.I)水平显著下降，而R.I的鞭毛蛋白可通过miR-223-3p/NLRP3信号转导抑制巨噬细胞内NLRP3炎症小体的激活和细胞焦亡，从而有效缓解溃疡性结肠炎的病情。在巨噬细胞中，GSDMD作为负调节因子调节环状GMP-AMP合成酶(cyclic GMP-AMP synthase，cGAS)依赖性炎症，从而起到控制结肠炎病情的作用；给予cGAS抑制剂可以缓解GSDMD缺陷小鼠的结肠炎[36]。姜黄素可上调沉默信息调节因子2相关蛋白1(silent information regulator 2-related protein 1，SIRT1)和核因子E2相关因子2(nuclear factor erythroid 2-related factor 2，NRF2)的表达，下调TLR4、NLRP3及caspase-1的表达。而SIRT1/NRF2通路的激活可抑制新生大鼠的TLR4信号通路，从而阻碍经典的细胞焦亡途径，改善坏死性结肠炎[37]。Caspase-8及其衔接子FADD可通过调节肠道免疫稳态改善IBD。其中，FADD可通过抑制混合激酶样蛋白(mixed-lineage kinase domain-like protein，MLKL)诱导的肠上皮细胞坏死和caspase-8-GSDMD依赖性肠上皮细胞焦亡，减少Z-DNA结合蛋白1(Z-DNA binding protein 1，ZBP1)和肿瘤坏死因子受体1(tumor necrosis factor receptor type 1，TNFR1)的激活，从而降低肠道炎症水平[38]。以上研究表明，姜黄素等一系列化合物可通过抑制肠道巨噬细胞或肠道上皮细胞焦亡缓解IBD。

2.3. 细胞焦亡与感染性肠炎

细胞焦亡与许多感染性疾病的发生和发展息息相关。非经典途径介导的细胞焦亡可以抑制胞内病原菌的增殖[39-40]。肠伤寒沙门杆菌可活化caspase-4/11，诱导感染肠伤寒沙门菌的肠道上皮细胞发生焦亡，并从肠道脱落。肠道上皮细胞中过表达的caspase-4可抑制胞内伤寒杆菌的增殖，而敲除caspase-4可促进伤寒杆菌的增殖[41]。在鼠伤寒沙门杆菌感染小肠上皮细胞和巨噬细胞而诱发形成的自限性肠胃炎中，III型分泌系统的效应因子参与细胞焦亡、细胞凋亡和细胞坏死的级联反应，干扰细菌的有效清除[42]。在肠道杆菌鼠疫耶尔森菌引起的感染性肠炎中，鼠疫耶尔森菌效应蛋白YOPJ抑制TAK1或核因子κB激酶，触发RIPK1-caspase-8依赖的GSDMD切割，这一作用机制可有效地帮助宿主抵御鼠疫耶尔森菌的感染[43-44]。在病毒感染的肠炎中，识别病毒dsRNA片段的NLRP9特异性表达于肠道上皮，并与接头蛋白ASC和caspase-1形成炎症小体复合物，促进GSDMD及IL-18的成熟，保护肠道上皮细胞免受轮状病毒感染[45]。然而，GSDMD在感染性疾病中并不总是具有保护作用，它也可加剧细菌感染。在致病性大肠杆菌感染时，GSDMD基因敲除小鼠的存活率高于对照组小鼠，其主要机制是敲除GSDMD基因后，中性粒细胞作为抵抗细菌入侵的主要细胞，具有更长的存活时间，从而增强宿主的抗感染能力[46-47]。由此可知，细胞焦亡在不同类型的感染性肠炎中发挥作用的方式不尽相同。肠道上皮细胞中发生的焦亡会引起病原菌的脱落和清除，而发生在免疫细胞中的焦亡则引起免疫细胞的减少和免疫应答的减弱。因此，应从适度调节细胞焦亡方面考虑感染性肠炎患者的最佳临床治疗方式。

2.4. 细胞焦亡与肠道肿瘤

研究[48]显示：程序性死亡配体1(programmed death-ligand 1，PD-L1)可将TNF-ɑ诱导的癌细胞凋亡切换为由caspase-8介导的非经典细胞焦亡。细胞毒性T淋巴细胞释放颗粒酶A(granzyme A，GZMA)裂解GSDMB，从而诱导肿瘤细胞发生焦亡，可用于靶向免疫消除肿瘤细胞[49]。当与抗程序性死亡受体1(programmed death-1，PD-1)联合使用时，人GSDMB重组蛋白质在小鼠结直肠癌细胞CT26和黑色素瘤细胞B16中的异位表达可促进肿瘤的清除。ΔNp63被认为是结直肠癌治疗的有效靶点，抑制长链非编码RNA(long noncoding RNA，lncRNA) RP1-85F18.6的表达可降低ΔNp63的表达，从而诱导结直肠癌细胞发生焦亡[50]。亚麻木酚素(secoisolariciresinol diglucoside，SDG)通过激活caspase-1，裂解结直肠癌细胞GSDMD，诱导焦亡[51]。凋亡素通过裂解caspase-3和GSDME，诱导移植HCT116细胞的裸鼠结肠癌细胞发生焦亡，显著抑制肿瘤生长[52]。此外，洛铂可通过激活caspase-3切割GSDME，诱导结肠癌细胞发生焦亡，还可以通过激活活性氧(reactive oxygen species，ROS)/c-Jun氨基端蛋白激酶(c-Jun N-terminal protein kainse，JNK)/Bax-线粒体凋亡途径，促进caspase-3/9活化下游的GSDME，诱导结肠癌细胞发生焦亡[53-54]。近期有研究[55-56]表明：新型抗肿瘤药物DMXAA通过激活干扰素基因刺激因子(stimulator of interferon genes，STING)介导的脾酪氨酸激酶(spleen tyrosine kinase，Syk)信号通路，诱导GSDMD裂解，进而促进肠道上皮肿瘤细胞焦亡，同时STING还可通过调节肠道肿瘤细胞的增殖、黏附、侵袭和炎症反应来调控结直肠癌的发生和发展。因此，深入了解细胞焦亡作用的分子途径，理清细胞焦亡与肿瘤之间复杂的联系，或有望将其应用于现有的或新的临床抗癌治疗。细胞焦亡与肠道炎性损伤及治疗的相关总结见表1。

表1.

细胞焦亡与肠道炎性损伤及治疗

Table 1 Pyroptosis in intestinal inflammatory damage and treatment

疾病类型

焦亡

途径

激活的

炎症小体

 参与的gasdermin蛋白

释放的

细胞因子

干预药物

或靶点

 干预机制

参考

文献

脓毒症

肠道损伤

经典

途径

 Caspase-1 GSDMD

HMGB1、

IL-1β、IL-18

 BRD4 抑制NF-κB的磷酸化和NLRP3/ASC/caspase-1复合体的激活 [26]

非经典

途径

 Caspase-11 CO

抑制caspase-11/GSDMD的裂解，

减轻脓毒症引起的肠黏膜损伤

 [27]

炎症性

肠病

经典

途径

 Caspase-1 GSDMD HMGB1、IL-1β、IL-18 姜黄素 通过上调SIRT1/NRF2的激活抑制TLR4信号通路，改善坏死性结肠炎 [36]

非经典

途径

 Caspase-8 GSDMD FADD FADD通过抑制caspase-8-GSDMD依赖的肠道上皮细胞焦亡，减轻ZBP1和TNFR1下游的肠道炎症反应 [37]

感染性

肠炎

经典

途径

 Caspase-1 GSDMD IL-18 NLRP9 NLRP9与ASC、caspase-1形成复合物，促进GSDMD、IL-18的成熟，使肠道上皮免受感染 [45]

非经典

途径

 Caspase-8 GSDMD IL-18 YOPJ YOPJ通过抑制TAK1或核因子κB激酶，触发RIPK1-caspase-8依赖的GSDMD切割，以抵御肠道耶尔森菌感染 [43-44]
疾病类型

焦亡

途径

激活的

炎症小体

 参与的gasdermin蛋白

释放的

细胞因子

干预药物或

靶点

 干预机制

参考

文献
肠道肿瘤

经典

途径

 Caspase-1 GSDMD SDG SDG在CRC中的抗癌活性与SDG通过ROS/PI3K/Akt/Bax-线粒体凋亡通路诱导GSDMD依赖性焦亡密切相关 [51]
Caspase-1 GSDMD

IL-1、

IL-18

 DMXAA

DMXAA激活STING/Syk信号通路诱导GSDMD裂解，促进肠道上皮肿瘤细胞

焦亡

 [55-56]

非经典

途径

 GZMA GSDMB GZMA与PD-1抗体联合使用 GZMA裂解GSDMB重组蛋白，促进肿瘤细胞焦亡，清除结直肠癌细胞 [49]
Caspase-3 GSDME 凋亡素 凋亡素通过裂解移植HCT116细胞的裸鼠caspase-3和GSDME，诱导结直肠癌细胞焦亡 [52]
Caspase-3/9 GSDME 洛铂 通过激活ROS/JNK/Bax-线粒体凋亡途径，促进caspase-3/9剪切GSDME，诱导结肠癌细胞焦亡 [53-54]
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HMGB1：高迁移率族蛋白1；IL：白介素；BRD4：溴结构域蛋白4；NF-κB：核因子κB；NLRP：核苷酸结合寡聚化结构域样受体蛋白；ASC：胱天蛋白酶募集域结构的凋亡相关斑点样蛋白；CO：一氧化碳；SIRT1：沉默信息调节因子2相关蛋白1；NRF2：核因子E2相关因子2；TLR4：Toll样受体4；FADD：Fas相关死亡结构域蛋白；ZBP1：Z-DNA结合蛋白1；TNFR1：肿瘤坏死因子受体1；TAK1：转化生长因子-β激活激酶1；RIPK1：受体相互作用蛋白激酶1；SDG：亚麻木酚素；CRC：结直肠癌；ROS：活性氧；PI3K：磷脂酰肌醇3激酶；DMXAA：5,6-二甲基蒽酮-4-乙酸(一种新型抗肿瘤药物)；STING：干扰素基因刺激因子；Syk：脾酪氨酸激酶；GZMA：颗粒酶A；PD-1：程序性死亡受体1；JNK：c-Jun氨基端蛋白激酶。

3. 展 望

随着对细胞焦亡相关生物学功能研究的广泛深入，发现细胞焦亡在多种肠道炎性损伤相关疾病的发病中发挥着重要作用，因而细胞焦亡可能为治疗这些疾病提供新的思路。细胞焦亡相关的激活剂或抑制剂在多种疾病动物模型中的成功应用，进一步引发了相关领域的研究热潮。但实验证明，仅从单方面着眼细胞焦亡对肠道炎性损伤的治疗往往不能取得令人满意的结果。现有的治疗方法对脓毒症肠道损伤、炎症性肠病、感染性肠炎、肠道肿瘤的效果亦不是十分理想。细胞焦亡对肠道疾病作用的准确定位及其机制仍须深入探究。细胞焦亡作为程序性死亡的一种新形式，其发生离不开caspase家族成员的驱动以及炎症小体的介导。肠道免疫细胞或上皮细胞通过细胞焦亡调控肠道炎性损伤的具体作用机制仍然存在许多值得探讨的问题，例如，GSDMD作为gasdermin家族成员，对于其膜孔的具体组装方式目前仍无一致意见；gasdermin家族成员是否均参与细胞焦亡调控的肠道炎性损伤；其在细胞焦亡过程中是否且如何被机体其他因子所调控；炎症小体的形成受多种刺激，但这些刺激因素是否具有显著的一致性，是否还有其他机制可以调节由LPS诱导的非经典细胞焦亡机制。细胞焦亡的复杂性，包括其在肠道炎性疾病中的作用和有效的激活剂或抑制剂，及其可能的临床应用价值，将继续吸引人们进行深入探究。这些探究可为肠道炎性损伤的有效防治提供新的理论依据和临床思路。

基金资助

国家自然科学基金(82100537)；湖南省卫生健康委员会课题(202110002229)。

This work was supported by the National Natural Science Foundation (82100537) and the Project of Health Comission of Hunan Province (202110002229), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

刘丹丹 论文构思，文献查阅，论文撰写与修改；钟小林、曹文宇 论文修改；陈玲 选题指导，论文审校。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202302252.pdf

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