Nature Reviews | 胃肠道中的炎症小体：感染，癌症和肠道微生物群稳态（完整版）
Abstract
Inflammasome signalling is an emerging pillar of innate immunity and has a central role in the regulation of gastrointestinal health and disease. Activation of the inflammasome complex mediates both the release of the pro-inflammatory cytokines IL-1β and IL-18 and the execution of a form of inflammatory cell death known as pyroptosis. In most cases, these mediators of inflammation provide protection against bacterial, viral and protozoal infections. However, unchecked inflammasome activities perpetuate chronic inflammation, which underpins the molecular and pathophysiological basis of gastritis, IBD, upper and lower gastrointestinal cancer, nonalcoholic fatty liver disease and obesity. Studies have also highlighted an inflammasome signature in the maintenance of gut microbiota and gut–brain homeostasis. Harnessing the immunomodulatory properties of the inflammasome could transform clinical practice in the treatment of acute and chronic gastrointestinal and extragastrointestinal diseases. This Review presents an overview of inflammasome biology in gastrointestinal health and disease and describes the value of experimental and pharmacological intervention in the treatment of inflammasome-associated clinical manifestations.
01
炎症小体复合物
炎症小体传感受器 NLRP1b，NLRP3，NLRC4，AIM2 和 pyrin 都能够形成含有衔接蛋白ASC和半胱氨酸蛋白酶 caspase 1 的经典炎症小体复合物。NLRP1b 和 NLRC4 也在没有 ASC 的情况下募集 caspase 1，因为它们的结构中存在 CARD结构域 [1-3] 。NLRP3 和 NLRC4 的激活分别需要 NEK7 激酶和 NLR 家族成员神经元凋亡抑制蛋白（NAIP）。
Caspase 1裂解前体细胞因子pro-IL-1β 和 pro-IL-18 以及成孔蛋白 gasdermin D。Gasdermin D 的活性片段寡聚化导致细胞膜上形成孔洞，引发细胞焦亡(pyroptosis) [4-11]。这些孔洞允许从细胞中被动释放具有生物活性的 IL-1β 和 IL-18。
非经典炎症小体的定义是需要人类 caspase 4 和 caspase 5 或小鼠caspase 11激活的 NLRP3 炎症小体复合物12。这些半胱天冬酶（Caspase）的活化导致 gasdermin D 的裂解和细胞焦亡 [4-6]。gasdermin D 的成孔片段（pore-forming fragment）激活 NLRP3 炎症小体以及 IL-1β 与 IL-18 的 caspase 1 依赖性成熟 [4,5]。
TIPs：
pyroptosis：细胞焦亡,是一种新的程序性细胞死亡方式，其特征为依赖于半胱天冬酶-1(caspase-1)，并伴有大量促炎症因子的释放。细胞焦亡的形态学特征、发生及调控机制等均不同于凋亡、坏死等其他细胞死亡方式[13]；
Caspase: 半胱天冬酶；
02
炎症小体识别胃肠道的细菌，病毒，原生动物(protozoa)和蠕虫(helminths)
病原体携带大量病原相关分子模式 (pathogen-associated molecular patterns, PAMPs)，这些 PAMPs 能够直接结合并且激活炎症小体感受器或诱导能被炎症小体感受器感知的细胞生理变化[1]。病原体也会对宿主细胞造成严重损害，从而诱导释放能够激活炎症小体的危险相关分子模式(danger-associated molecular patterns, DAMPs) [2]。
TIPs：
AIM2(absent in melanoma 2): 黑色素瘤缺乏因子2；
ASC(apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD)): 含有半胱天冬酶激活和募集结构域 (CARD) 的凋亡相关斑点样蛋白质；
LPS(lipopolysaccharide): 脂多糖；
NAIP(neuronal apoptosis inhibitory protein): 神经细胞凋亡抑制蛋白；
NLRC4: nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) family CARD domain-containing protein 4NLRP3: NACHT, LRR and PYD domains-containing protein 3；
ROS(reactive oxygen species): 活性氧；
T3SS(type 3 secretion system): 3 型分泌系统。
03
炎症小体和其相关的分子在肠道细胞和免疫细胞中促进杀死和清除胃肠道病原菌
a | 炎症小体通过诱导 IL-1β 和 IL-18 的分泌和细胞焦亡介导保护宿主免受革兰氏阴性菌侵袭[1-8]。NLRP6 和 NLRP12 可以负向调节炎症[9-12]。NLRP6 在杯状细胞(goblet cells)中对 Toll 样受体诱导的自噬作出响应从而介导粘液的分泌[13]。RNA 结合的 DEAH 盒蛋白9(RNA-bound DEAH box protein 9, DHX9)与 NLRP9b 相互作用，诱导炎症小体复合物的组装[14]。NLRP6–DHX15 复合物结合病毒 RNA 并且诱导 1 型和 3 型干扰素的产生[15]。
b | 肠道巨噬细胞可以区分病原菌和共生菌[16]。
c | Caspase 1，caspase 8 或者 caspase 11 的激活可导致细胞死亡，进而促使肠上皮中被感染的上皮细胞被清除和排出[17-19]。
d | 炎症小体可以通过抑制细菌摄入减少细菌负荷，这会限制巨噬细胞的运动和刚度(stiffness)并且促进活性氧的产生(ROS) [20]。焦亡的巨噬细胞释放完整的细菌或者被截留在细胞内陷阱的细菌[21]，这些释放的实体会进一步被中性粒细胞吞噬[3,22] 。
TIPs：
pyroptosis：细胞焦亡,是一种新的程序性细胞死亡方式，其特征为依赖于半胱天冬酶-1(caspase-1)，并伴有大量促炎症因子的释放。细胞焦亡的形态学特征、发生及调控机制等均不同于凋亡、坏死等其他细胞死亡方式01；
Caspase：半胱天冬酶；
ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD) ：含有半胱天冬酶激活和募集结构域的凋亡相关斑点样蛋白；
dsRNA, double-stranded RNA：双链 RNA ；
EMCV, encephalomyocarditis virus：脑心肌炎病毒；
KC，keratinocyte chemoattractant：角质形成细胞化学引诱物（也称为CXCL1）；
MAVS, mitochondrial antiviral-signalling protein：线粒体抗病毒信号蛋白；
NAIP, neuronal apoptosis inhibitory protein：神经细胞凋亡抑制蛋白；
NF-κB, nuclear factor-κB：核因子-κB；
NLRC4, nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) family CARD domain-containing protein 4 ：核苷酸结合结构域，富含亮氨酸重复序列的蛋白(NLR)家族 CARD 结构域蛋白4(NLRC4)；
ssRNA, single-stranded RNA ：单链RNA。
04
炎症小体-微生物群轴调节肠道炎症和癌症的发展
a | 诸如氧化偶氮甲烷(AOM)和葡聚糖硫酸钠(DSS)等致瘤因素会引起损伤，导致危险相关分子模式(DAMPs)的释放。同时，细菌可侵入肠细胞并将病原体相关分子模式(PAMPs)引入宿主细胞。炎症小体可以感知DAMPs和PAMPs[1-6] 。IL-18促进可溶性 IL-22结合蛋白(IL-22BP)的下调，可溶性IL-22结合蛋白可以控制肠道中IL-22抑制炎症或诱导肠道肿瘤发生的能力[7]。
b | 核苷酸结合结构域，富含亮氨酸重复序列的蛋白(NLR)家族CARD结构域蛋白 4(NLRC4)和神经细胞凋亡抑制蛋白(NAIPs)可阻断细胞增殖和肿瘤发生[8,9]。
c | DNA依懒性蛋白激酶(DNA-PK)通过激活AKT(activate RAC serine/threonine-protein kinase) 和转录因子MYC诱导结直肠肿瘤发生[10,11]。该过程会被黑色素瘤缺乏因子 2(AIM2)抑制。AIM2也可以诱导肠道上皮细胞产生抗菌肽(AMPs)以调节肠道微生物群[12,13]。研究表明NLRC3具有类似的负向调节作用[14]。
d | NLRP6和NLRP12在胃肠道感染，急性结肠炎和结直肠癌的发病机制中也发挥作用[15-24]。
问号表示未知的调节物质。
TIPs：
NLRC4, Nucleotide-binding domain, leucine-rich repeat-containing protein (NLR) family CARD domain-containing protein 4 (NLRC4)： 核苷酸结合结构域，富含亮氨酸重复序列的蛋白(NLR)家族 CARD 结构域蛋白4；
NAIPs, neuronal apoptosis inhibitory proteins：神经细胞凋亡抑制蛋白；
GFR：生长因子受体；
mTOR：雷帕霉素的机制目标；
NLRP(NACHT, LRR and PYD domains-containing protein)含 NACHT，LRR和PYD结构域的蛋白质；
PI3Ks：磷酸肌醇3-激酶；
ROS：活性氧；
STAT3：信号转导和转录激活因子3；
T3SS：3型分泌系统；
TLR：Toll样受体。
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