2023, Vol. 50扩展功能
文章信息
- 任颖, 李亚博, 薛岩松, 韩北忠
- REN Ying, LI Yabo, XUE Yansong, HAN Beizhong
- 食源性致病菌激活NLRP3炎症小体及食源性功能物质的抑制机理研究进展
- Activation of NLRP3 inflammasome by foodborne pathogens and the inhibitory mechanisms of functional food substances: a comprehensive review
- 微生物学通报, 2023, 50(5): 2173-2190
- Microbiology China, 2023, 50(5): 2173-2190
- DOI: 10.13344/j.microbiol.china.220818
-
文章历史
- 收稿日期: 2022-08-28
- 接受日期: 2022-12-09
- 网络首发日期: 2023-01-11
机体通过模式识别受体(pattern-recognition receptors, PRRs)来监测体内稳态，识别入侵宿主的病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)、损伤相关分子模式(damage-associated molecular patterns, DAMPs)和稳态改变过程(homeostasis-altering molecular processes, HAMPs)，进而引起炎症反应[1]。PRRs包括多种家族成员[2]，其中位于胞内的NOD样受体家族3 (nucleotide binding oligomerization domain-like receptors, NLRP3)炎症小体是研究最广泛透彻的一种。NLRP3炎症小体由NLRP3感受器、凋亡相关斑点样衔接蛋白(apoptosis- associated speck-like protein containing a caspase- recruitment domain, ASC)和半胱氨酸天冬氨酸蛋白酶-1 (cysteinyl aspartate specific proteinase-1, caspase-1)组成，是一种多聚蛋白复合物，是先天性免疫系统的重要组成部分，在防御病原体感染中起重要作用[3]。NLRP3炎症小体作为胞内信号反应平台，可被PAMPs和DAMPs等多种刺激物触发激活，NLRP3炎症小体组装后剪切无活性酶原形式的caspase-1 (pro-caspase-1)蛋白成活性形式，进而切割gasdermin D蛋白在细胞膜上形成孔洞，促进白细胞介素-1β (interleukin-1β, IL-1β)和白细胞介素-18 (interleukin-18, IL-18)等促炎因子的成熟和大量分泌，导致细胞焦亡[4-5]。NLRP3炎症小体参与宿主对病原体感染的防御，促进促炎细胞因子的成熟和释放，从而抵抗病原体感染，在许多食源性致病微生物引起的疾病病理中发挥重要作用。然而，不同致病微生物诱导NLRP3炎症小体激活的分子机制是复杂多样的，并且NLRP3炎症小体的过度异常激活会引起机体剧烈的炎症反应，有些甚至导致死亡，因此，了解食源性病原体感染诱导NLRP3炎症小体激活的机制，对于抵抗这些致病菌介导的炎症性疾病极为重要。许多病原菌如大肠杆菌、金黄色葡萄球菌中已存在高度耐抗生素的菌株，抗生素滥用带来的细菌耐药性问题已十分严重，依靠大量使用抗生素从而降低致病菌带来的炎症反应已不能完全解决问题，因此，挖掘天然、高效和安全的抑制炎症过度活化的活性物质迫在眉睫。许多食源性物质中提取的功能化合物如葡萄籽原花青素、没食子酸、白藜芦醇、萝卜硫素和姜黄素等均已被鉴定为NLRP3炎症小体抑制剂[6-8]。天然产物如冬凌草甲素和荜茇酰胺等特异性抑制NLRP3炎症小体激活的功能已被广泛报道，这些物质通过干扰炎症小体的组装过程阻断NLRP3炎症小体的活性[9-10]。因此，挖掘这些天然产物和膳食物质调控NLRP3炎症小体，从而抵抗食源性致病菌介导的炎症反应具有极为重要的研究意义。
1 NLRP3炎症小体的激活机制NLRP3炎症小体的激活需要两个步骤，首先是启动阶段，其中，核因子-κB (nuclear factor kappa-B, NF-κB)信号通路在启动过程中发挥了关键的作用。当Toll样受体(Toll-like receptor, TLR)、NLR (NOD1和NOD2)等受体的配体或某些细胞因子激活NF-κB信号通路后，启动NLRP3、pro-IL-1β蛋白的转录过程，上调炎症小体相关蛋白表达水平[11]。接下来，激活阶段需要通过激活信号进行刺激诱导，DAMPs和PAMPs包括细胞外ATP、成孔毒素、RNA病毒和晶体微粒物质等刺激信号通过诱导NLRP3蛋白的去泛素化促进ASC寡聚化的形成等过程，实现NLRP3炎症小体的自组装[4]，这些刺激信号通常会引起细胞稳态紊乱进而激活NLRP3炎症小体(图 1)，目前其造成的细胞应激现象有3种类型。
|
| 图 1 NLRP3炎症小体的双信号激活模型 Figure 1 A two-signal model for NLRP3 inflammasome activation. NLRP3炎症小体的激活需要2种信号分子介导：信号1通常为微生物分子如脂多糖或内源性细胞因子，通过激活NF-κB信号通路，上调NLRP3和pro-IL-1β的表达；信号2通常为细菌毒素、明矾、二氧化硅和尿酸晶体等属于DAMPs和PAMPs的刺激物，通过引起细胞内K+外流、Ca2+内流和细胞器损伤等过程导致NLRP3炎症小体的组装 Activation of the NLRP3 inflammasome requires two signals: Signal 1 is provided by microbial molecules such as LPS or endogenous cytokines and leads to the upregulation of NLRP3 and pro-IL-1β through the activation of the NF-κB pathway; Signal 2 is the irritant of DAMPs and PAMPs, such as bacterial toxins, alum, silica and uric acid crystal, causing K+ efflux, Ca2+ influx and organelle damage, leading to assembly of NLRP3 inflammasome. |
|
|
据报道，ATP和许多细菌成孔毒素诱导NLRP3炎症小体激活的过程中均会伴随着K+外流的现象[12-13]，并且在细胞外添加高浓度氯化钾后抑制了ATP、尼日利亚霉素和尿酸盐等刺激物对NLRP3炎症小体的激活作用[14]。因此，通常认为细胞内K+浓度下降是NLRP3炎症小体激活的共同机制。然而，咪喹莫特和CL097小分子激活NLRP3不需要K+流出，而且咪喹莫特诱导的ASC寡聚、caspase-1活化和IL-1β分泌未被胞外高浓度氯化钾阻断[15]，表明K+外流并不是NLRP3炎症小体激活的一个必要条件。K+外流激活炎症小体的具体机制可能是和NIMA相关激酶7 (NIMA-related kinase 7, NEK7)蛋白有关，K+外流促进NLRP3-NEK7相互作用，NEK7促进ASC斑点形成和caspase-1激活[16]，所以NEK7将有望成为治疗与NLRP3炎症小体相关炎症疾病的靶点。
1.2 线粒体损伤和ROS产生大量研究将线粒体确定为控制先天免疫和炎症反应的核心细胞器，线粒体紊乱是慢性炎症相关疾病的关键致病机制[17]。受损线粒体产生的线粒体ROS (mitochondrial ROS, mtROS)和线粒体DNA (mitochondrial DNA, mtDNA)已被证明可以介导炎症反应，激活NLRP3炎症小体[17-19]。研究表明尿路致病性大肠杆菌的α-溶血素促进NLRP3蛋白的去泛素化、寡聚化，破坏线粒体功能，激活NLRP3炎症小体[20]。大肠杆菌O157:H7通过type 3 secretion system (T3SS)破坏线粒体，影响电子传递链复合物的活性，从而激活NLRP3炎症小体[21-22]，使用ROS清除剂处理细胞后会显著降低NLRP3的活化[21, 23]。此外，对线粒体自噬的药理调节可以靶向清除受损线粒体，负向调节NLRP3炎症小体从而发挥抗炎作用[18, 21, 24]。由此可见，调节线粒体功能紊乱、抑制ROS的大量产生通常是限制NLRP3炎症小体激活的主要靶点。
1.3 溶酶体破坏硅盐和铝盐晶体被细胞吞噬后通常会导致溶酶体损伤和溶酶体膜破裂，造成组织蛋白酶B释放，激活NLRP3炎症小体[23]。抑制溶酶体酸化或组织蛋白酶B活性会削弱NLRP3的激活[25]。有研究表明，组织蛋白酶B抑制剂CA-074-Me能有效缓解金黄色葡萄球菌毒素对NLRP3的激活作用，减弱IL-1β的释放[26]。因此，溶酶体破坏对NLRP3炎症小体的激活起重要作用，并且晶体颗粒物质和溶酶体损伤二肽LL-OMe触发NLRP3炎症小体活化的同时也会引起K+的流出，K+外流被抑制后，颗粒物对NLRP3炎症小体的激活也被阻断[12]。类似的研究表明，在胞外添加高浓度氯化钾后能稳定线粒体并抑制组织蛋白酶B的释放[20, 26]，由此可见，不同机制之间上下游关系需要进一步研究确认。
总而言之，NLRP3炎症小体的激活是一个复杂的过程，食源性致病菌及其毒素诱导NLRP3炎症小体激活的过程中通常伴随着上述3种机制的发生，只有明确病原微生物激活炎症小体引起炎症反应的具体机制，才能针对性地开发以NLRP3炎症小体为靶点抑制食源性致病菌介导的炎症反应的膳食成分。
2 食源性致病菌激活NLRP3炎症小体NLRP3炎症小体可被PAMPs和DAMPs等刺激物触发激活，食源性致病菌及其产生的各种毒素是一类典型的PAMPs，感染后往往引起严重的食源性疾病，因此，探究食源性病原体感染诱导NLRP3炎症小体激活的机制对于抵抗这些致病菌介导的炎症性疾病极为重要。表 1中列举了激活NLRP3炎症小体的常见食源性致病菌。
| 食源性致病菌及代谢产物 Foodborne pathogens and metabolites |
激活机制 Activation mechanism |
参考文献 Reference |
|
| 金黄色葡萄球菌 Staphylococcus aureus |
杀白细胞素A/B Leukocidin A/B |
K+外流 K+ efflux |
[27] |
| 金黄色葡萄球菌液 Staphylococcus aureus |
K+外流、ASC寡聚化 K+ efflux, ASC oligomerization |
[28-30] | |
| α-溶血素 α-hemolysin |
结合ADAM10形成七聚体、K+外流、ROS产生、ASC寡聚化 Bind ADAM10 to form heptamers, K+ efflux, ROS production, ASC oligomerization |
[31-34] | |
| 葡萄球菌肠毒素A Staphylococcal Enterotoxin A |
上调NLRP3炎症小体组分蛋白表达 Up-regulation of NLRP3 inflammasome protein expression |
[35] | |
| PV杀白细胞素 Panton-valentine leukocidin |
K+外流 K+ efflux |
[26] | |
| 产气荚膜梭菌 Clostridium perfringens |
β1毒素 β1 toxin |
K+外流 K+ efflux |
[36] |
| 溶血素O Perfringolysin O |
K+外流 K+ efflux |
[37] | |
| 蜡样芽孢杆菌Bacillus cereus | 溶血素BL Hemolysin BL |
K+外流 K+ efflux |
[38] |
| 非溶血性肠毒素 Non-hemolytic enterotoxin |
K+外流 K+ efflux |
[39] | |
| 蜡样芽孢杆菌H2菌株 Bacillus cereus H2 strain |
ROS产生、Ca2+内流、溶酶体破裂、组织蛋白酶 释放 ROS production, Ca2+ influx, lysosomal disruption, cathepsin release |
[40] | |
| 单核细胞增生李斯特氏菌 Listeria monocytogenes |
李斯特菌溶血素O Listeriolysin O |
NF-κB、MAPK信号通路活化，ROS产生，ASC 寡聚化 NF-κB, MAPK signaling pathway activation, ROS production, ASC oligomerization |
[41-43] |
| 大肠杆菌 Escherichia coli |
大肠杆菌O157:H7 Escherichia coli O157:H7 |
ROS产生 ROS production |
[21] |
| 大肠杆菌O104:H4, Escherichia coli O104:H4 |
ROS产生 ROS production |
[44] | |
| CNF1毒素 CNF1 toxin |
激酶Pak1磷酸化NLRP3的Thr 659位点 The kinase Pak1 phosphorylates the Thr 659 site of NLRP3 |
[45] | |
| 肠致病性大肠杆菌 Enteropathogenic Escherichia coli |
Ⅲ型分泌系统 Type 3 secretion system |
[46] | |
金黄色葡萄球菌是常见的食源性致病微生物，由于抗生素的滥用使其具有很强的耐药性，尤其是耐甲氧西林金黄色葡萄球菌已经成为最主要的耐药病原体[47]。金黄色葡萄球菌可以释放多种毒素从而介导多种食源性疾病的发生，成孔毒素α-、β-、γ-溶血素、PV杀白细胞素(panton- valentine leukocidin, PVL)和杀白细胞素AB (leukocidin AB, LukAB)等是其关键致病毒力因子[48]，并且不同毒素对不同物种及不同细胞系的敏感度不一样，因此，金黄色葡萄球菌成孔毒素可能根据宿主的种类发挥不同的作用[26-27]。
已有研究发现金黄色葡萄球菌菌液中的α-、β-和γ-溶血素可激活NLRP3炎症小体，诱导caspase-1活化，促进IL-1β分泌介导细胞焦亡，但这一过程是在金黄色葡萄球菌脂蛋白存在的情况下发生的，脂蛋白可充当NLRP3炎症小体的第一启动信号，促进pro-IL-1β蛋白的表达[28]。体内和体外研究均发现NLRP3炎症小体的激活是α-溶血素(α-hemolysin, Hla)引起金黄色葡萄球菌肺炎的主要机制[31]。此外，Hla可引起胞内过量ROS的产生和ASC斑点化的形成[32]，敲除溶血活性的Hla突变体则不会激活NLRP3炎症小体[49]。有报道称Hla可结合金属蛋白酶10 (ADAM10)在细胞膜上形成七聚体，导致细胞质内容物流出和小分子流入细胞，并且ADAM10的表达水平对Hla激活NLRP3至关重要[33-34]。Hla毒素除了诱导NLRP3炎症小体的激活，还能引起溶酶体酶酸性鞘磷脂酶的激活和神经酰胺的形成，神经酰胺可增加溶酶体的通透性和组织蛋白酶B和D释放到细胞质中，介导NLRC4炎症小体的激活，导致IL-1β的形成释放[50]。
此外，金黄色葡萄球菌的另一大成孔毒素LukAB通过与膜上CD11b受体结合[51]，促进caspase-1活化和IL-1β分泌，诱导人单核细胞死亡[27]。PVL是一种双组分白细胞毒素，由2种不同的蛋白质LukS-PV和LukF-PV组成[52]。PVL通过促进组织蛋白酶B的释放介导NLRP3炎症小体的激活，单独使用LukS-PV或LukF-PV刺激细胞并无IL-1β的释放，只有两者组合才能发挥作用[26]。PVL是K+载体，会引起胞内的K+外流，并且胞外添加氯化钾后组织蛋白酶B的激活受到抑制，说明在PVL诱导的NLRP3炎症体激活过程中K+外流可能是溶酶体破坏的上游信号[26]。细胞外囊泡(extracellular vesicles, EV)是金黄色葡萄球菌的独特的分泌系统，EV内包裹着成孔毒素和脂蛋白等多种金黄色葡萄球菌的致病毒力因子，EV将其运送至宿主细胞内激活NLRP3炎症小体，促进IL-1β和IL-18的释放，引起细胞焦亡[29]。此外，金黄色葡萄球菌感染巨噬细胞时，脾酪氨酸激酶(spleen tyrosine kinase, Syk)和c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)磷酸化水平迅速上升，增加了NEK7-NLRP3复合物的形成，促进ASC斑点化的形成及caspase-1、IL-1β的活化，并且这些过程被胞外高浓度氯化钾所抑制[30]。
金黄色葡萄球菌分泌的肠毒素(staphylococcal enterotoxin A, SEA)显著上调了NLRP3炎症小体组分蛋白的表达，通过NF-κB/MAPK途径激活NLRP3炎症小体[35]。肠毒素(staphylococcal enterotoxin O, SEO)在ATP作用下引起NLRP3炎症小体的激活和IL-1β分泌，并且这一过程依赖于K+外流[53]，肠毒素SEO则充当启动信号的作用。类似地，金黄色葡萄球菌的毒性休克综合征毒素-1 (toxic shock syndrome toxin 1, TSST-1)毒素和ATP促进小鼠腹腔巨噬细胞NLRP3的组装，引起IL-1β的成熟和释放[54]。
2.1.2 产气荚膜梭菌产气荚膜梭菌是一种广泛分布于自然界的条件性致病菌，可引起人类及动物食物中毒、创伤性气性坏疽、坏死性肠炎和肠毒血症等疾病[55]。该菌产生的20多种复杂的毒素在其致病性中扮演了重要角色[56]。通过分析小鼠肌肉坏死感染组织中细菌病原体的基因表达，发现TLR2和NLRP3炎症小体相关基因表达上调[57]，表明产气荚膜梭菌可能参与宿主炎症免疫的调控。产气荚膜梭菌β1毒素是C型产气荚膜梭菌诱导出血性肠坏死病变的重要毒力因子，是一种成孔毒素，能够在易感细胞质膜上形成孔洞，从而导致K+流出、Ca2+流入，并导致细胞吸水涨破[36]。已有研究得出，重组产气荚膜梭菌β1毒素诱导RAW264.7和THP-1等巨噬细胞通过依赖caspase-1的经典细胞焦亡途径诱导巨噬细胞发生焦亡[36]。α-毒素是A型产气荚膜梭菌表达量最高也是最重要的毒素，是造成肌肉气性坏疽的最主要毒力因子[56]。在肌肉感染产气荚膜梭菌的小鼠模型中发现，不仅是α-毒素，产气荚膜梭菌溶血素O (perfringolysin O, PFO)毒素也部分参与了肌肉气性坏疽疾病的进展，而且证明了PFO介导的肌坏死依赖于NLRP3，在体外实验中也证明了PFO而不是α-毒素在巨噬细胞中触发了NLRP3炎症小体的激活[37]。
2.1.3 蜡样芽孢杆菌蜡样芽孢杆菌感染可诱导宿主产生炎症反应，是食物中毒的主要诱因[58]，在其分泌的一系列毒力因子中，2种成孔毒素溶血素BL (hemolysin BL, HBL)和非溶血性肠毒素(non-hemolytic enterotoxin, NHE)尤为重要。HBL和NHE都是由3个亚基组成的多组分毒素，单一或者两个亚基组合并不能激活NLRP3炎症小体，只有3个亚基同时存在并且3个亚基都以线性或特定的顺序在细胞膜上组装形成孔洞，进而诱导K+外流，才能诱导NLRP3炎症小体的激活，介导细胞焦亡[38-39]。因此，只有明确致病菌的致病机理才能明确其激活炎症小体的具体机制，为将来有针对性地抑制致病菌引起的炎症反应提供科学依据。此外，蜡样芽孢杆菌菌株H2是从南海深海冷泉中石蟹的刚毛中分离鉴定到的，该菌株具有较强的感染性，能诱导多种类型细胞死亡；报道称蜡样芽孢杆菌菌株H2上调巨噬细胞内JNK信号通路的磷酸化水平，H2菌株感染伴随着胞内ROS的释放、Ca2+内流和溶酶体破裂及组织蛋白酶的释放[40]，进而诱导NLRP3炎症小体的活化。
2.1.4 单核细胞增生李斯特氏菌单核细胞增生李斯特氏菌感染能引起急性胃肠炎、菌血症和脑膜炎等疾病，是一种常见的食源性病原菌[59-60]。其成孔毒素李斯特菌溶血素O (listeriolysin O, LLO)是主要致病毒素，可帮助菌体从吞噬体逃逸到宿主胞浆中，在单增李斯特菌诱导的疾病发病机制中起着至关重要的作用[61]。单增李斯特菌感染可激活巨噬细胞中的多种炎症小体，包括NLRP3、AIM2和NLRC4[62-63]。单增李斯特菌感染BV2小胶质细胞过程中，NF-κB、MAPK信号通路被活化，引起大量ROS的释放，激活NLRP3炎症小体[41]。进一步研究表明，LLO毒素在诱导NLRP3炎症小体活化中起关键作用，其结构域中的苏氨酸残基LLO T223是诱导炎症小体激活的关键位点，LLO T223促进ASC的Y144氨基酸残基磷酸化，进而诱导ASC寡聚化，通过Syk信号激活NLRP3炎症小体[42]。在单增生李斯特菌感染巨噬细胞过程中，两种与炎症相关的激酶表达上调，两者通过JNK途径促进NEK7和NLRP3之间的相互作用，介导NLRP3炎症小体的激活[43]。
2.2 革兰氏阴性菌大肠杆菌O157:H7和大肠杆菌O104:H4通过损伤线粒体产生大量ROS，诱导宿主NLRP3炎症小体激活[21, 44]。来自致病性大肠杆菌的细胞毒性坏死因子-1 (cytotoxic necrotizing factor-1, CNF1)是一种靶向Rho-GTP酶的毒素，CNF1通过p21活化激酶1和2 (Pak1/2)介导NLRP3炎症小体激活，激酶Pak1使NLRP3的Thr 659位点磷酸化，进而触发NLRP3炎症小体的激活，而且NLRP3在Thr 659位点的磷酸化过程是NLRP3-NEK7相互作用所必需的步骤[45]。此外，肠致病性大肠杆菌(enteropathogenic Escherichia coli, EPEC)依赖T3SS的方式在人单核细胞来源的巨噬细胞和THP-1细胞中导致NLRP3炎症小体的激活、细胞焦亡和促炎细胞因子释放[46]。
3 功能成分对病原菌诱导的NLRP3炎症小体的抑制作用抗生素可抑制致病菌的生长繁殖过程，减缓其引起的剧烈炎症反应，但抗生素产生的耐药性问题不容忽视。膳食来源的功能成分被证明可以降低罹患多种致病微生物引起的疾病风险[64]。如表没食子儿茶素没食子酸酯(epigallocatechin gallate, EGCG)可结合细菌细胞膜破坏脂质层，抑制金黄色葡萄球菌和大肠杆菌的活性[65]。中草药中含有许多生物活性成分，从中可提取生物碱、萜类等天然产物[66]，这些天然产物常被用于和抗生素协同治疗致病菌感染[67]。益生菌定殖肠道黏膜表面形成生物菌膜，通过分泌各种代谢产物降低肠道pH，抑制食源性致病菌的定殖与入侵[68]。其中也有很多食源性成分可以有效抑制炎症小体诱导的炎症反应，我们将从膳食天然产物的角度总结膳食功能性化合物抑制致病微生物引起的NLRP3炎症小体激活的机制(表 2)。
| 食源性致病菌 Foodborne pathogens |
功能物质 Functional substances |
抑制机制 Inhibitory mechanism |
参考文献 Reference |
| 金黄色葡萄球菌 Staphylococcus aureus |
硒、桑叶提取物、白藜芦醇 Selenium, mulberry leaf extract, resveratrol |
抑制ROS产生、抑制NLRP3组分蛋白 Inhibit ROS, inhibit NLRP3 component proteins |
[69-73] |
| 和厚朴酚 Honokiol |
抑制NLRP3组分蛋白、拮抗Hla毒素 溶血性和自组装的膜通道 Inhibit NLRP3 component proteins, inhibit Hla toxin hemolysis and self-assembly of membrane channels |
[74] | |
| 表没食子儿茶素没食子酸酯 Epigallocatechin gallate |
抑制ROS释放、ASC寡聚化和NLRP3-ASC的结合过程 拮抗Hla毒溶血性及Hla毒素寡聚化过程 Inhibit ROS, ASC oligomerization and NLRP3-ASC binding Inhibit Hla toxin hemolysis and Hla toxin oligomerization |
[32] | |
| 大肠杆菌 Escherichia coli |
鼠李糖乳杆菌GR-1 Lactobacillus rhamnosus GR-1 |
增强线粒体自噬、抑制ROS产生、下调NLRP3和ASC 蛋白表达 Enhance mitophagy, inhibit ROS, downregulate NLRP3 and ASC |
[75-77] |
| 丁酸梭菌 Clostridium butyricum |
下调NLRP3和caspase-1蛋白的表达 Downregulate NLRP3 and caspase-1 |
[78] | |
| 约氏乳杆菌L531 Lactobacillus johnsonii L531 |
促进细胞自噬、抑制NF-κB信号通路 Promote autophagy and inhibit NF-κB signaling pathway |
[79] | |
| 白藜芦醇、铁皮石斛多糖 Resveratrol, Dendrobium officinale polysaccharides |
降低ROS的水平，提高线粒体膜电位， 抑制NF-κB信号通路 Reduce ROS, increase the mitochondrial membrane potential, inhibit NF-κB signaling pathway |
[61, 80] | |
| 红树莓提取物 Raspberry extract |
激活Nrf2信号通路 Activate the Nrf2 signaling pathway |
[81] | |
| 槲皮素 Quercetin |
保护线粒体、清除ROS、增强自噬 Protect mitochondria, scavenge ROS, enhance autophagy |
[21] | |
| 单增李斯特菌 Listeria monocytogenes |
隐丹参酮 Cryptotanshinone |
抑制NLRP3炎症小体组分蛋白的表达、 抑制MAPK信号通路、抑制K+外流和ASC寡聚化 Inhibit the NLRP3 inflammasome component proteins, Inhibit MAPK signaling pathway, inhibit K+ efflux and ASC oligomerization |
[82-83] |
| 铜绿假单胞菌 Pseudomonas aeruginosa |
槲皮素 Quercetin |
抑制MAPK信号通路、减弱NLRP3、caspase-1蛋白表达 Inhibit MAPK signaling pathway, NLRP3, caspase-1 protein |
[84] |
| 异硫氰酸苄酯 Benzyl isothiocyanate |
抑制MAPK、NF-κB信号通路 Inhibit MAPK, NF-κB signaling pathway |
[85] | |
| 幽门螺杆菌 Helicobacter pylori |
查尔酮衍生物 Chalcone derivatives |
阻断NF-κB信号通路 Inhibit NF-κB signaling pathway |
[86] |
| 醉茄素A、委陵菜酸 Withaferin A, valerian acid |
抑制NF-κB信号通路 Inhibit NF-κB signaling pathway |
[87-88] | |
| 裸花紫珠 Callicarpa nudiflora |
抑制NLRP3和caspase-1的表达，降低ROS产生 Inhibit NLRP3 and caspase-1, inhibit ROS |
[89] | |
| 广藿香醇 Patchouli alcohol |
稳定线粒体膜电位，降低ROS产生 Stabilize mitochondrial membrane potential and reduce ROS |
[90] | |
| 萝卜硫素 Sulforaphane |
降低炎症蛋白表达，清除ROS Reduce inflammatory protein and scavenge ROS |
[91] |
硒是人体重要的微量营养素，广泛存在于蔬菜中[92]。研究表明硒能抑制NLRP3炎症小体组分蛋白的表达和ROS的产生，减轻金黄色葡萄球菌引起的乳腺炎[69]。许多研究表明硒元素能通过抑制TLR4/NF-κB信号通路来减轻炎症反应，在NLRP3炎症小体激活的启动阶段发挥重要作用，因此，硒元素可能通过抑制NF-κB信号通路抑制NLRP3炎症小体组分蛋白的表达，从而减轻金黄色葡萄球菌感染引起的炎症反应[69-70]。桑叶提取物可抑制NLRP3炎症小体组分蛋白的表达并激活核因子E2相关因子2 (nuclear factorerythroid 2-related factor 2, Nrf2)抗氧化信号通路，缓解金黄色葡萄球菌诱导的结膜炎[71]。类似地，白藜芦醇、和厚朴酚、EGCG等天然多酚物质以及二苯基嘧啶(含N原子的杂环化合物，重要的药效基团)均显著降低金黄色葡萄球菌感染模型中的NLRP3、ASC和caspase-1的蛋白表达水平，抑制促炎细胞因子的释放[32, 72-74]。而且，EGCG处理还减少了Hla诱导的胞内ROS的释放和ASC斑点的形成，减弱了NLRP3和ASC的结合，进而抑制了NLRP3炎症小体的激活[32]。此外，EGCG与和厚朴酚均拮抗了Hla的产生和溶血活性[32, 74]。和厚朴酚阻碍了Hla组装时的膜通道，但不损害Hla寡聚化过程[74]，而EGCG与Hla结合阻止了Hla七聚体的自组装过程[32]。
3.2 针对大肠杆菌诱导的NLRP3炎症小体激活 3.2.1 益生菌益生菌如鼠李糖乳杆菌GR-1可显著下调子宫内膜细胞中NLRP3和ASC蛋白的表达水平，具有免疫调节潜力[75]。研究表明GR-1可通过增强线粒体自噬抑制ROS产生，减轻大肠杆菌诱导的NLRP3炎症小体活化[76]。GR-1在大肠杆菌感染的乳腺上皮细胞中抑制NLRP3和NLRC4炎症小体的激活，减少IL-lβ和IL-18的产生[77]。丁酸梭菌则通过下调产肠毒素大肠杆菌K88感染的肠道细胞中NLRP3和caspase-1的表达降低炎症反应[78]。约氏乳杆菌L531通过抑制NLRP3炎症小体活性和促进乳腺上皮细胞自噬改善大肠杆菌诱导的细胞损伤[79]。另外，约氏乳杆菌L531通过抑制TLR4/NF-κB/NLRP3炎症小体信号通路来减轻鼠伤寒沙门氏菌诱导的NLRP3炎症小体的过度激活，降低促炎细胞因子的表达[93]。此外，一些革兰氏阴性的非食源性致病菌分泌的内毒素脂多糖(LPS)，有可能通过和细胞膜表面TLR4受体结合或者通过G–的外膜囊泡转运至细胞内，激活caspase-11，进而导致K+外流，间接激活NLRP3炎症小体[5]。但它们未造成机体免疫系统紊乱的原因可能是免疫系统可以通过独特的识别方式区分致病菌和非致病菌。
3.2.2 多酚与多糖白藜芦醇可降低大肠埃希菌O104:H4感染引起的细胞内ROS的水平升高，提高线粒体膜电位，抑制NLRP3蛋白和IL-1β的表达水平[61]。铁皮石斛多糖减轻了致病性大肠杆菌诱导的巨噬细胞焦亡，显著降低了ROS的产生，抑制了NLRP3炎症小体的激活[80]。大肠杆菌O157:H7感染破坏细胞内线粒体功能，减弱细胞自噬造成受损线粒体和ROS的大量累积，而槲皮素处理则逆转了这一过程，进而抑制NLRP3炎症小体的激活[21]。红树莓提取物则通过激活Nrf2抗氧化信号通路抑制NLRP3炎症小体活化，进而抑制了大肠杆菌O157:H7介导的炎症反应[81]，但其抑制炎症小体激活的具体有效化合物还需进一步分析和验证。NLRP3炎症小体除了受到启动相关信号通路的调控之外，靶向其蛋白结构从而抑制其下游组装过程是未来需要加大研究的方向和难点，这些靶点的发现和突破将有望用于更多的炎症疾病治疗。由此可见，槲皮素虽然作为ROS的有效清除剂可以抑制NLRP3炎症小体诱导的炎症反应，但其是否直接作用于炎症小体本身还有待进一步明确。
3.3 针对单增李斯特菌诱导的NLRP3炎症小体激活隐丹参酮是一种天然醌类化合物，具有抗肿瘤、保护内脏器官等多种药理活性[82]，通常靶向NF-κB信号通路发挥抗炎作用。在单增李斯特菌感染的细胞中，隐丹参酮能抑制胞内NLRP3炎症小体组分蛋白的表达和MAPK信号通路的活化，抑制LLO毒素引起的K+外流和ASC的寡聚化过程，在单增李斯特菌的感染中发挥抗炎作用[83]，已经有研究表明隐丹参酮还能阻断Ca2+信号传导和线粒体ROS的产生，特异性抑制NLRP3炎症小体的激活[94]。
3.4 针对铜绿假单胞菌诱导的NLRP3炎症小体激活铜绿假单胞菌能形成细胞外膜囊泡输送毒素扰乱线粒体功能，诱导K+外排，进而激活NLRP3炎症小体[95]。槲皮素能通过抑制MAPK信号通路减弱NLRP3、caspase-1蛋白表达水平，从而减少由铜绿假单胞菌引起的胞内IL-1β的释放[84]。类似地，异硫氰酸苄酯常存在于十字花科蔬菜中，而且具有抗肿瘤作用的天然物质，能抑制MAPK、NF-κB和NLRP3炎症小体信号通路，减弱铜绿假单胞菌LPS和ATP诱导的IL-1β的产生[85]。
3.5 针对幽门螺杆菌诱导的NLRP3炎症小体激活幽门螺杆菌感染是胃癌的主要诱因，细胞毒素相关基因A (cytotoxin associated gene A, CagA)和空泡细胞毒素A (vacuolating cytotoxin A, VacA)是幽门螺杆菌感染的主要致病毒力因子，可造成细胞线粒体功能障碍，诱导产生大量ROS，激活NLRP3炎症小体[96]。查尔酮是合成类黄酮的前体物质，具有抗癌、抗炎、抗氧化等多种生物活性[97]。查尔酮衍生物阻断NF-κB信号通路，抑制幽门螺杆菌诱导的NLRP3炎症小体的激活[86]。并且甘草查尔酮B已被证明直接与NEK7蛋白结合，干扰NLRP3与NEK7的相互作用和ASC寡聚化过程，抑制NLRP3炎症小体活化[98]。醉茄素A (withaferin A)是从南非醉茄中分离的甾体内酯[99]，其能抑制幽门螺杆菌感染BMDC细胞中的NF-κB信号通路，降低NLRP3蛋白的转录水平，抑制IL-1β和caspase-1的活化过程[87]。类似地，木瓜三萜中一种重要活性物质委陵菜酸对幽门螺杆菌感染的细胞中ROS和促炎因子的产生均有明显降低作用，减少了TLR4/NF-κB/NLRP3炎症小体信号通路相关蛋白的表达[88]。裸花紫珠(Callicarpa nudiflora)是一种传统中草药，能减少幽门螺杆菌诱导GES-1细胞的NLRP3和caspase-1的表达，降低ROS和各种炎症因子的产生，抑制NLRP3炎症小体的激活[89]。广藿香醇能稳定线粒体膜电位，降低ROS产生来保护GES-1细胞免受幽门螺杆菌诱导的线粒体损伤。通过对NLRP3和caspase-1蛋白的共定位分析发现，广藿香醇可能抑制了NLRP3炎症小体组装过程[90]。萝卜硫素是异硫氰酸盐的一种，其能通过降低炎症蛋白表达、清除ROS、稳定线粒体缓解幽门螺杆菌诱导的细胞炎症反应[91]。而且萝卜硫素已经被研究证明能独立于Nrf2信号通路来抑制多种炎症小体的激活[100]，所以大量存在于十字花科蔬菜中的异硫氰酸盐类天然物质具有极大的抗炎研究价值。
综上所述，许多膳食功能成分和药用植物提取物能够抑制食源性致病菌诱导的NLRP3炎症小体活化，其中大部分化合物抑制炎症小体的第一启动信号通路，特异性不强。少部分是通过直接靶向NLRP3炎症小体自组装过程，抑制NLRP3炎症小体的激活通路，具有很强的研究价值，因此，深入了解其分子机制和临床安全性将为其治疗炎性疾病奠定基础。
4 结论与展望食源性致病菌感染通常引起机体严重的免疫反应，造成NLRP3炎症小体的异常激活，从而诱导许多炎症性疾病的发生，所以明确病原体对NLRP3炎症小体的激活和调节机制至关重要。另外，预防和治疗食源性致病菌引起的炎症反应时，NLRP3炎症小体可作为干预的潜在靶标，但NLRP3炎症小体的一些小分子抑制剂存在生物利用率低等问题，如小分子抑制剂YQ128的口服生物利用度仅为10%，大大限制了其临床应用[101]。因此，探索新型的NLRP3抑制剂也具有广泛的应用前景。一些天然植物化合物及膳食多酚等功能化合物可获得性强、安全性高，抗炎功能已被广泛报道，它们控制食源性致病菌引起的炎症反应具有很大的研究价值。通过调控NLRP3炎症小体从而调节宿主免疫反应，可能成为抗生素的辅助治疗手段。但大多的研究仅停留在实验室验证层次，并且大多停留在体外细胞研究层面，因此还需要进一步开展临床研究探索。此外，通过对化学合成小分子抑制剂的研究，可以依据其结构和对接靶点，为寻找其他天然安全的食源性NLRP3炎症小体抑制剂提供理论依据。因此，深入了解食源性致病菌激活炎症小体，以及食源性功能活性物质抑制炎症小体的机理，将有望在食源性功能物质和天然产物方面发掘具有前景的治疗炎症手段。
| [1] |
LISTON A, MASTERS SL. Homeostasis-altering molecular processes as mechanisms of inflammasome activation[J]. Nature Reviews Immunology, 2017, 17(3): 208-214. DOI:10.1038/nri.2016.151 |
| [2] |
KUMAR H, KAWAI T, AKIRA S. Pathogen recognition by the innate immune system[J]. International Reviews of Immunology, 2011, 30(1): 16-34. DOI:10.3109/08830185.2010.529976 |
| [3] |
LATZ E, XIAO TS, STUTZ A. Activation and regulation of the inflammasomes[J]. Nature Reviews Immunology, 2013, 13(6): 397-411. DOI:10.1038/nri3452 |
| [4] |
KELLEY N, JELTEMA D, DUAN YH, HE Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation[J]. International Journal of Molecular Sciences, 2019, 20(13): 3328. DOI:10.3390/ijms20133328 |
| [5] |
XUE YS, ENOSI TUIPULOTU D, TAN WH, KAY C, MAN SM. Emerging activators and regulators of inflammasomes and pyroptosis[J]. Trends in Immunology, 2019, 40(11): 1035-1052. DOI:10.1016/j.it.2019.09.005 |
| [6] |
ÖZENVER N, EFFERTH T. Phytochemical inhibitors of the NLRP3 inflammasome for the treatment of inflammatory diseases[J]. Pharmacological Research, 2021, 170: 105710. DOI:10.1016/j.phrs.2021.105710 |
| [7] |
OLCUM M, TASTAN B, ERCAN I, ELTUTAN IB, GENC S. Inhibitory effects of phytochemicals on NLRP3 inflammasome activation: a review[J]. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 2020, 75: 153238. DOI:10.1016/j.phymed.2020.153238 |
| [8] |
LIN YQ, LUO TY, WENG AL, HUANG XD, YAO YQ, FU Z, LI YW, LIU AJ, LI XC, CHEN DF, PAN H. Gallic acid alleviates gouty arthritis by inhibiting NLRP3 inflammasome activation and pyroptosis through enhancing Nrf2 signaling[J]. Frontiers in Immunology, 2020, 11: 580593. DOI:10.3389/fimmu.2020.580593 |
| [9] |
HE HB, JIANG H, CHEN Y, YE J, WANG AL, WANG C, LIU QS, LIANG GL, DENG XM, JIANG W, ZHOU RB. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity[J]. Nature Communications, 2018, 9: 2550. DOI:10.1038/s41467-018-04947-6 |
| [10] |
SHI J, XIA Y, WANG HH, YI ZJ, ZHANG RR, ZHANG XF. Piperlongumine is an NLRP3 inhibitor with anti-inflammatory activity[J]. Frontiers in Pharmacology, 2022, 12: 818326. DOI:10.3389/fphar.2021.818326 |
| [11] |
BAUERNFEIND FG, HORVATH G, STUTZ A, ALNEMRI ES, MacDONALD K, SPEERT D, FERNANDES-ALNEMRI T, WU JH, MONKS BG, FITZGERALD KA, HORNUNG V, LATZ E. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression[J]. The Journal of Immunology, 2009, 183(2): 787-791. DOI:10.4049/jimmunol.0901363 |
| [12] |
MUÑOZ-PLANILLO R, KUFFA P, MARTÍNEZ-COLÓN G, SMITH BL, RAJENDIRAN TM, NÚÑEZ G. K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter[J]. Immunity, 2013, 38(6): 1142-1153. DOI:10.1016/j.immuni.2013.05.016 |
| [13] |
JING WD, LO PILATO J, KAY C, MAN SM. Activation mechanisms of inflammasomes by bacterial toxins[J]. Cellular Microbiology, 2021, 23(4): e13309. |
| [14] |
PÉTRILLI V, PAPIN S, DOSTERT C, MAYOR A, MARTINON F, TSCHOPP J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration[J]. Cell Death & Differentiation, 2007, 14(9): 1583-1589. |
| [15] |
GROß CJ, MISHRA R, SCHNEIDER KS, MÉDARD G, WETTMARSHAUSEN J, DITTLEIN DC, SHI HX, GORKA O, KOENIG PA, FROMM S, MAGNANI G, ĆIKOVIĆ T, HARTJES L, SMOLLICH J, ROBERTSON AAB, COOPER MA, SCHMIDT-SUPPRIAN M, SCHUSTER M, SCHRODER K, BROZ P, et al. K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria[J]. Immunity, 2016, 45(4): 761-773. DOI:10.1016/j.immuni.2016.08.010 |
| [16] |
HE Y, ZENG MY, YANG DH, MOTRO B, NÚÑEZ G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux[J]. Nature, 2016, 530(7590): 354-357. DOI:10.1038/nature16959 |
| [17] |
MISSIROLI S, GENOVESE I, PERRONE M, VEZZANI B, VITTO VAM, GIORGI C. The role of mitochondria in inflammation: from cancer to neurodegenerative disorders[J]. Journal of Clinical Medicine, 2020, 9(3): 740. DOI:10.3390/jcm9030740 |
| [18] |
MISHRA SR, MAHAPATRA KK, BEHERA BP, PATRA S, BHOL CS, PANIGRAHI DP, PRAHARAJ PP, SINGH A, PATIL S, DHIMAN R, BHUTIA SK. Mitochondrial dysfunction as a driver of NLRP3 inflammasome activation and its modulation through mitophagy for potential therapeutics[J]. The International Journal of Biochemistry & Cell Biology, 2021, 136: 106013. |
| [19] |
ZHOU RB, YAZDI AS, MENU P, TSCHOPP J. A role for mitochondria in NLRP3 inflammasome activation[J]. Nature, 2011, 469(7329): 221-225. DOI:10.1038/nature09663 |
| [20] |
VERMA V, KUMAR P, GUPTA S, YADAV S, DHANDA RS, THORLACIUS H, YADAV M. α-Hemolysin of uropathogenic E. coli regulates NLRP3 inflammasome activation and mitochondrial dysfunction in THP-1 macrophages[J]. Scientific Reports, 2020, 10: 12653. DOI:10.1038/s41598-020-69501-1 |
| [21] |
XUE YS, DU M, ZHU MJ. Quercetin suppresses NLRP3 inflammasome activation in epithelial cells triggered by Escherichia coli O157: H7[J]. Free Radical Biology and Medicine, 2017, 108: 760-769. DOI:10.1016/j.freeradbiomed.2017.05.003 |
| [22] |
XUE YS, DU M, ZHU MJ. Quercetin prevents Escherichia coli O157: H7 adhesion to epithelial cells via suppressing focal adhesions[J]. Frontiers in Microbiology, 2019, 9: 3278. DOI:10.3389/fmicb.2018.03278 |
| [23] |
DOSTERT C, PÉTRILLI V, VAN BRUGGEN R, STEELE C, MOSSMAN BT, TSCHOPP J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica[J]. Science, 2008, 320(5876): 674-677. DOI:10.1126/science.1156995 |
| [24] |
IP WKE, HOSHI N, SHOUVAL DS, SNAPPER S, MEDZHITOV R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages[J]. Science, 2017, 356(6337): 513-519. DOI:10.1126/science.aal3535 |
| [25] |
HORNUNG V, BAUERNFEIND F, HALLE A, SAMSTAD EO, KONO H, ROCK KL, FITZGERALD KA, LATZ E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization[J]. Nature Immunology, 2008, 9(8): 847-856. DOI:10.1038/ni.1631 |
| [26] |
HOLZINGER D, GIELDON L, MYSORE V, NIPPE N, TAXMAN DJ, DUNCAN JA, BROGLIE PM, MARKETON K, AUSTERMANN J, VOGL T, FOELL D, NIEMANN S, PETERS G, ROTH J, LÖFFLER B. Staphylococcus aureus panton-valentine leukocidin induces an inflammatory response in human phagocytes via the NLRP3 inflammasome[J]. Journal of Leukocyte Biology, 2012, 92(5): 1069-1081. DOI:10.1189/jlb.0112014 |
| [27] |
MELEHANI JH, JAMES DBA, DuMONT AL, TORRES VJ, DUNCAN JA. Staphylococcus aureus leukocidin A/B (LukAB) kills human monocytes via host NLRP3 and ASC when extracellular, but not intracellular[J]. PLoS Pathogens, 2015, 11(6): e1004970. DOI:10.1371/journal.ppat.1004970 |
| [28] |
MUÑOZ-PLANILLO R, FRANCHI L, MILLER LS, NÚÑEZ G. A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome[J]. Journal of Immunology (Baltimore, Md: 1950), 2009, 183(6): 3942-3948. DOI:10.4049/jimmunol.0900729 |
| [29] |
WANG XG, EAGEN WJ, LEE JC. Orchestration of human macrophage NLRP3 inflammasome activation by Staphylococcus aureus extracellular vesicles[J]. Proceedings of the National Academy of Sciences of the United States of America, 2020, 117(6): 3174-3184. DOI:10.1073/pnas.1915829117 |
| [30] |
LIU RQ, LIU YS, LIU C, GAO AJ, WANG L, TANG HX, WU Q, WANG X, TIAN DR, QI Z, SHEN YN. NEK7-mediated activation of NLRP3 inflammasome is coordinated by potassium efflux/syk/JNK signaling during Staphylococcus aureus infection[J]. Frontiers in Immunology, 2021, 12: 747370. DOI:10.3389/fimmu.2021.747370 |
| [31] |
KEBAIER C, CHAMBERLAND RR, ALLEN IC, GAO X, BROGLIE PM, HALL JD, JANIA C, DOERSCHUK CM, TILLEY SL, DUNCAN JA. Staphylococcus aureus α-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome[J]. The Journal of Infectious Diseases, 2012, 205(5): 807-817. DOI:10.1093/infdis/jir846 |
| [32] |
LIU CM, HAO K, LIU ZJ, LIU ZH, GUO N. Epigallocatechin gallate (EGCG) attenuates staphylococcal alpha-hemolysin (Hla)-induced NLRP3 inflammasome activation via ROS-MAPK pathways and EGCG-Hla interactions[J]. International Immunopharmacology, 2021, 100: 108170. DOI:10.1016/j.intimp.2021.108170 |
| [33] |
SUGAWARA T, YAMASHITA D, KATO K, PENG Z, UEDA J, KANEKO J, KAMIO Y, TANAKA Y, YAO M. Structural basis for pore-forming mechanism of staphylococcal α-hemolysin[J]. Toxicon: Official Journal of the International Society on Toxinology, 2015, 108: 226-231. DOI:10.1016/j.toxicon.2015.09.033 |
| [34] |
EZEKWE EAD Jr, WENG CY, DUNCAN JA. ADAM10 cell surface expression but not activity is critical for Staphylococcus aureus α-hemolysin-mediated activation of the NLRP3 inflammasome in human monocytes[J]. Toxins, 2016, 8(4): 95. DOI:10.3390/toxins8040095 |
| [35] |
LIU CM, CHI KM, YANG M, GUO N. Staphylococcal enterotoxin A induces intestinal barrier dysfunction and activates NLRP3 inflammasome via NF-κB/MAPK signaling pathways in mice[J]. Toxins, 2022, 14(1): 29. DOI:10.3390/toxins14010029 |
| [36] |
SHI KS. The mechanism of pyroptosis induced by Clostridium perfringens β1 toxin in macrophages[D]. Yinchuan: Master's Thesis of Ningxia University, 2020 (in Chinese). 史客松. 产气荚膜梭菌β1毒素诱导巨噬细胞焦亡机制的研究[D]. 银川: 宁夏大学硕士学位论文, 2020. |
| [37] |
YAMAMURA K, ASHIDA H, OKANO T, KINOSHITA-DAITOKU R, SUZUKI S, OHTANI K, HAMAGAKI M, IKEDA T, SUZUKI T. Inflammasome activation induced by perfringolysin O of Clostridium perfringens and its involvement in the progression of gas gangrene[J]. Frontiers in Microbiology, 2019, 10: 2406. DOI:10.3389/fmicb.2019.02406 |
| [38] |
MATHUR A, FENG SY, HAYWARD JA, NGO C, FOX D, ATMOSUKARTO II, PRICE JD, SCHAUER K, MÄRTLBAUER E, ROBERTSON AAB, BURGIO G, FOX EM, LEPPLA SH, KAAKOUSH NO, MAN SM. A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome[J]. Nature Microbiology, 2019, 4(2): 362-374. |
| [39] |
FOX D, MATHUR A, XUE YS, LIU YQ, TAN WH, FENG SY, PANDEY A, NGO C, HAYWARD JA, ATMOSUKARTO II, PRICE JD, JOHNSON MD, JESSBERGER N, ROBERTSON AAB, BURGIO G, TSCHARKE DC, FOX EM, LEYTON DL, KAAKOUSH NO, MÄRTLBAUER E, et al. Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome[J]. Nature Communications, 2020, 11: 760. DOI:10.1038/s41467-020-14534-3 |
| [40] |
ZHAO Y, JIANG S, ZHANG J, GUAN XL, SUN BG, SUN L. A virulent Bacillus cereus strain from deep-sea cold seep induces pyroptosis in a manner that involves NLRP3 inflammasome, JNK pathway, and lysosomal rupture[J]. Virulence, 2021, 12(1): 1362-1376. DOI:10.1080/21505594.2021.1926649 |
| [41] |
YUAN L, ZHU YR, HUANG S, LIN L, JIANG XG, CHEN SX. NF-κB/ROS and ERK pathways regulate NLRP3 inflammasome activation in Listeria monocytogenes infected BV2 microglia cells[J]. Journal of Microbiology, 2021, 59(8): 771-781. DOI:10.1007/s12275-021-0692-9 |
| [42] |
TANISHITA Y, SEKIYA H, INOHARA N, TSUCHIYA K, MITSUYAMA M, NÚÑEZ G, HARA H. Listeria toxin promotes phosphorylation of the inflammasome adaptor ASC through Lyn and Syk to exacerbate pathogen expansion[J]. Cell Reports, 2022, 38(8): 110414. DOI:10.1016/j.celrep.2022.110414 |
| [43] |
GAO AJ, TANG HX, ZHANG Q, LIU RQ, WANG L, LIU YS, QI Z, SHEN YN. Mst1/2-ALK promotes NLRP3 inflammasome activation and cell apoptosis during Listeria monocytogenes infection[J]. Journal of Microbiology, 2021, 59(7): 681-692. DOI:10.1007/s12275-021-0638-2 |
| [44] |
DENG L, TIAN J. Resveratrol suppresses NLRP3 inflammasome activation in colonic epithelial cells triggered by Escherichia coli O104: H4[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2021, 26(2): 167-173. (in Chinese) 邓莉, 田静. 白藜芦醇抑制大肠埃希菌O104: H4诱导的结肠上皮细胞NLRP3炎症小体活化[J]. 中国临床药理学与治疗学, 2021, 26(2): 167-173. |
| [45] |
DUFIES O, DOYE A, COURJON J, TORRE C, MICHEL G, LOUBATIER C, JACQUEL A, CHAINTREUIL P, MAJOOR A, GUINAMARD RR, GALLERAND A, SAAVEDRA PHV, VERHOEYEN E, REY A, MARCHETTI S, RUIMY R, CZERUCKA D, LAMKANFI M, PY BF, MUNRO P, et al. Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice[J]. Nature Microbiology, 2021, 6(3): 401-412. DOI:10.1038/s41564-020-00832-5 |
| [46] |
GODDARD PJ, SANCHEZ-GARRIDO J, SLATER SL, KALYAN M, RUANO-GALLEGO D, MARCHÈS O, FERNÁNDEZ LÁ, FRANKEL G, SHENOY AR. Enteropathogenic Escherichia coli stimulates effector-driven rapid caspase-4 activation in human macrophages[J]. Cell Reports, 2019, 27(4): 1008-1017.e6. DOI:10.1016/j.celrep.2019.03.100 |
| [47] |
TURNER NA, SHARMA-KUINKEL BK, MASKARINEC SA, EICHENBERGER EM, SHAH PP, CARUGATI M, HOLLAND TL, FOWLER VG. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research[J]. Nature Reviews Microbiology, 2019, 17(4): 203-218. DOI:10.1038/s41579-018-0147-4 |
| [48] |
TAM K, TORRES VJ. Staphylococcus aureus secreted toxins and extracellular enzymes[J]. Microbiology Spectrum, 2019, 7(2). |
| [49] |
CRAVEN RR, GAO X, ALLEN IC, GRIS D, BUBECK WARDENBURG J, MCELVANIA-TEKIPPE E, TING JP, DUNCAN JA. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells[J]. PLoS One, 2009, 4(10): e7446. DOI:10.1371/journal.pone.0007446 |
| [50] |
MA J, GULBINS E, EDWARDS MJ, CALDWELL CC, FRAUNHOLZ M, BECKER KA. Staphylococcus aureus α-toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides[J]. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 2017, 43(6): 2170-2184. DOI:10.1159/000484296 |
| [51] |
MELEHANI JH, DUNCAN JA. Inflammasome Activation Can Mediate Tissue-specific Pathogenesis or Protection in Staphylococcus aureus Infection[M]. Current Topics in Microbiology and Immunology. Cham: Springer International Publishing, 2016: 257-282.
|
| [52] |
LÖFFLER B, HUSSAIN M, GRUNDMEIER M, BRÜCK M, HOLZINGER D, VARGA G, ROTH J, KAHL BC, PROCTOR RA, PETERS G. Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils[J]. PLoS Pathogens, 2010, 6(1): e1000715. DOI:10.1371/journal.ppat.1000715 |
| [53] |
HOU FQ, PENG LC, JIANG JL, CHEN TT, XU DY, HUANG QY, YE C, PENG YY, HU DL, FANG RD. ATP facilitates staphylococcal enterotoxin O induced neutrophil IL-1β secretion via NLRP3 inflammasome dependent pathways[J]. Frontiers in Immunology, 2021, 12: 649235. DOI:10.3389/fimmu.2021.649235 |
| [54] |
PENG LC, JIANG JL, CHEN TT, XU DY, HOU FQ, HUANG QY, PENG YY, YE C, HU DL, FANG RD. Toxic shock syndrome toxin 1 induces immune response via the activation of NLRP3 inflammasome[J]. Toxins, 2021, 13(1): 68. DOI:10.3390/toxins13010068 |
| [55] |
SHRESTHA A, UZAL FA, McCLANE BA. Enterotoxic clostridia: Clostridium perfringens enteric diseases[J]. Microbiology Spectrum, 2018, 6(5). |
| [56] |
UZAL FA, VIDAL JE, McCLANE BA, GURJAR AA. Clostridium perfringens toxins involved in mammalian veterinary diseases[J]. The Open Toxinology Journal, 2010, 2: 24-42. |
| [57] |
LOW LY, HARRISON PF, GOULD J, POWELL DR, CHOO JM, FORSTER SC, CHAPMAN R, GEARING LJ, CHEUNG JK, HERTZOG P, ROOD JI. Concurrent host-pathogen transcriptional responses in a Clostridium perfringens murine myonecrosis infection[J]. mBio, 2018, 9(2): e00473-e00418. |
| [58] |
ENOSI TUIPULOTU D, MATHUR A, NGO C, MAN SM. Bacillus cereus: epidemiology, virulence factors, and host-pathogen interactions[J]. Trends in Microbiology, 2021, 29(5): 458-471. DOI:10.1016/j.tim.2020.09.003 |
| [59] |
CLARK SE, SCHMIDT RL, MCDERMOTT DS, LENZ LL. A Batf3/Nlrp3/IL-18 axis promotes natural killer cell IL-10 production during Listeria monocytogenes infection[J]. Cell Reports, 2018, 23(9): 2582-2594. DOI:10.1016/j.celrep.2018.04.106 |
| [60] |
MEGLI C, MOROSKY S, RAJASUNDARAM D, COYNE CB. Inflammasome signaling in human placental trophoblasts regulates immune defense against Listeria monocytogenes infection[J]. The Journal of Experimental Medicine, 2021, 218(1): e20200649. DOI:10.1084/jem.20200649 |
| [61] |
MEIXENBERGER K, PACHE F, EITEL J, SCHMECK B, HIPPENSTIEL S, SLEVOGT H, N'GUESSAN P, WITZENRATH M, NETEA MG, CHAKRABORTY T, SUTTORP N, OPITZ B. Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1beta, depending on listeriolysin O and NLRP3[J]. Journal of Immunology (Baltimore, Md: 1950), 2010, 184(2): 922-930. DOI:10.4049/jimmunol.0901346 |
| [62] |
WU JH, FERNANDES-ALNEMRI T, ALNEMRI ES. Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes[J]. Journal of Clinical Immunology, 2010, 30(5): 693-702. DOI:10.1007/s10875-010-9425-2 |
| [63] |
KIM S, BAUERNFEIND F, ABLASSER A, HARTMANN G, FITZGERALD KA, LATZ E, HORNUNG V. Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome[J]. European Journal of Immunology, 2010, 40(6): 1545-1551. DOI:10.1002/eji.201040425 |
| [64] |
ZHANG H, TSAO R. Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects[J]. Current Opinion in Food Science, 2016, 8: 33-42. DOI:10.1016/j.cofs.2016.02.002 |
| [65] |
IKIGAI H, NAKAE T, HARA Y, SHIMAMURA T. Bactericidal catechins damage the lipid bilayer[J]. Biochimica et Biophysica Acta, 1993, 1147(1): 132-136. DOI:10.1016/0005-2736(93)90323-R |
| [66] |
ZOU K, LI Z, ZHANG Y, ZHANG HY, LI B, ZHU WL, SHI JY, JIA Q, LI YM. Advances in the study of berberine and its derivatives: a focus on anti-inflammatory and anti-tumor effects in the digestive system[J]. Acta Pharmacologica Sinica, 2017, 38(2): 157-167. DOI:10.1038/aps.2016.125 |
| [67] |
CHENG JD, WANG HZ, WANG J, XU YS, ZHANG L. Progress in natural products with anti-MRSA activities[J]. World Notes on Antibiotics, 2022, 43(4): 233-240, 255. (in Chinese) 程敬东, 王合珍, 王京, 徐应淑, 张磊. 具有抗MRSA活性的天然产物研究进展[J]. 国外医药(抗生素分册), 2022, 43(4): 233-240, 255. |
| [68] |
MOUSAVI KHANEGHAH A, ABHARI K, EŞ I, SOARES MB, OLIVEIRA RBA, HOSSEINI H, REZAEI M, BALTHAZAR CF, SILVA R, CRUZ AG, RANADHEERA CS, Sant'ANA AS. Interactions between probiotics and pathogenic microorganisms in hosts and foods: a review[J]. Trends in Food Science & Technology, 2020, 95: 205-218. |
| [69] |
BI CL, ZHANG SJ, SHEN YZ, PAULINE M, LI H, TANG H. Selenium plays an anti-inflammatory role by regulation NLRP3 inflammasome in Staphylococcus aureus-infected mouse mammary gland[J]. Biological Trace Element Research, 2021, 199(2): 604-610. DOI:10.1007/s12011-020-02166-z |
| [70] |
YANG Y, LV SJ, WANG ZN, LIU JJ. Selenium ameliorates S. aureus-induced inflammation in bovine mammary epithelial cells by regulating ROS-induced NLRP3 inflammasome[J]. Biological Trace Element Research, 2022, 200(7): 3171-3175. DOI:10.1007/s12011-021-02924-7 |
| [71] |
CHEN Y, LAI LL, MO ZT, LI X, SU XT, LI YQ, LENG EN, ZHANG YY, LI WN. Mulberry leaf extract alleviates Staphylococcus aureus-induced conjunctivitis in rabbits via downregulation of NLRP3 inflammasome and upregulation of the Nrf2 system and suppression of pro-inflammatory cytokines[J]. Pharmacology, 2022, 107(5/6): 250-262. |
| [72] |
WU SX, HUANG JN. Resveratrol alleviates Staphylococcus aureus pneumonia by inhibition of the NLRP3 inflammasome[J]. Experimental and Therapeutic Medicine, 2017, 14(6): 6099-6104. |
| [73] |
DUAN W, QIN F, WU D, DAI Y. Diphenyl pyrimidine exhibits protective effect on Staphylococcus aureus pneumonia in rat model by targeting NLRP3 expression[J]. Microbial Pathogenesis, 2021, 161: 105168. DOI:10.1016/j.micpath.2021.105168 |
| [74] |
GUO N, LIU ZJ, YAN ZQ, LIU ZH, HAO K, LIU CB, WANG J. Subinhibitory concentrations of Honokiol reduce α-Hemolysin (Hla) secretion by Staphylococcus aureus and the Hla-induced inflammatory response by inactivating the NLRP3 inflammasome[J]. Emerging Microbes & Infections, 2019, 8(1): 707-716. |
| [75] |
LIU N, WANG X, SHAN Q, XU L, LI YN, CHU BX, YANG L, WANG JF, ZHU YH. Lactobacillus rhamnosus ameliorates multi-drug-resistant Bacillus cereus-induced cell damage through inhibition of NLRP3 inflammasomes and apoptosis in bovine endometritis[J]. Microorganisms, 2022, 10(1): 137. DOI:10.3390/microorganisms10010137 |
| [76] |
LI YN, ZHU YH, CHU BX, LIU N, CHEN SY, WANG JF. Lactobacillus rhamnosus GR-1 prevents Escherichia coli-induced apoptosis through PINK1/parkin-mediated mitophagy in bovine mastitis[J]. Frontiers in Immunology, 2021, 12: 715098. DOI:10.3389/fimmu.2021.715098 |
| [77] |
WU Q, ZHU YH, XU J, LIU X, DUAN C, WANG MJ, WANG JF. Lactobacillus rhamnosus GR-1 ameliorates Escherichia coli-induced activation of NLRP3 and NLRC4 inflammasomes with differential requirement for ASC[J]. Frontiers in Microbiology, 2018, 9: 1661. DOI:10.3389/fmicb.2018.01661 |
| [78] |
LI HH, LI YP, ZHU Q, QIAO JY, WANG WJ. Dietary supplementation with Clostridium butyricum helps to improve the intestinal barrier function of weaned piglets challenged with enterotoxigenic Escherichia coli K88[J]. Journal of Applied Microbiology, 2018, 125(4): 964-975. DOI:10.1111/jam.13936 |
| [79] |
ZOU YJ, XU JJ, WANG X, ZHU YH, WU Q, WANG JF. Lactobacillus johnsonii L531 ameliorates Escherichia coli-induced cell damage via inhibiting NLRP3 inflammasome activity and promoting ATG5/ATG16L1-mediated autophagy in Porcine mammary epithelial cells[J]. Veterinary Sciences, 2020, 7(3): 112. DOI:10.3390/vetsci7030112 |
| [80] |
ZHANG XY, YAN YF, LV YX, LI X, CHEN LY, HUANG ZH, ZHOU JB, WANG Y, WANG XM, WANG X, GU HW. Dendrobium officinale polysaccharides attenuate uropathogenic Escherichia coli (UPEC)-induced pyroptosis in macrophage cells[J]. Biomedicine & Pharmacotherapy, 2022, 151: 113098. |
| [81] |
XUE YS, DU M, ZHU MJ. Raspberry extract prevents NLRP3 inflammasome activation in gut epithelial cells induced by pathogenic Escherichia coli[J]. Journal of Functional Foods, 2019, 56: 224-231. DOI:10.1016/j.jff.2019.03.005 |
| [82] |
WU YH, WU YR, LI B, YAN ZY. Cryptotanshinone: a review of its pharmacology activities and molecular mechanisms[J]. Fitoterapia, 2020, 145: 104633. DOI:10.1016/j.fitote.2020.104633 |
| [83] |
LU GJ. The mechanism in the protection of cryptotanshinone against infection by Listeria monocytogenes[D]. Changchun: Doctoral Dissertation of Jilin University, 2020 (in Chinese). 卢葛锦. 隐丹参酮对单增李斯特菌感染的保护作用及机制研究[D]. 长春: 吉林大学博士学位论文, 2020. |
| [84] |
CHANJITWIRIYA K, ROYTRAKUL S, KUNTHALERT D. Quercetin negatively regulates IL-1β production in Pseudomonas aeruginosa-infected human macrophages through the inhibition of MAPK/NLRP3 inflammasome pathways[J]. PLoS One, 2020, 15(8): e0237752. DOI:10.1371/journal.pone.0237752 |
| [85] |
PARK WS, LEE J, NA G, PARK S, SEO SK, CHOI JS, JUNG WK, CHOI IW. Benzyl isothiocyanate attenuates inflammasome activation in Pseudomonas aeruginosa LPS-stimulated THP-1 cells and exerts regulation through the MAPKs/NF-κB pathway[J]. International Journal of Molecular Sciences, 2022, 23(3): 1228. DOI:10.3390/ijms23031228 |
| [86] |
CHOI HR, LIM H, LEE JH, PARK H, KIM HP. Interruption of Helicobacter pylori-induced NLRP3 inflammasome activation by chalcone derivatives[J]. Biomolecules & Therapeutics, 2021, 29(4): 410-418. |
| [87] |
KIM JE, LEE JY, KANG MJ, JEONG YJ, CHOI JA, OH SM, LEE KB, PARK JH. Withaferin A inhibits Helicobacter pylori-induced production of IL-1β in dendritic cells by regulating NF-κB and NLRP3 inflammasome activation[J]. Immune Network, 2015, 15(6): 269-277. DOI:10.4110/in.2015.15.6.269 |
| [88] |
HE HB, ZHU LJ, HE JY, JIANG WJ, WANG X, PENG X, CHEN YT, SONG LH, ZHANG JH, ZOU K. Protective effect of tormentic acid on Helicobacter pylori induced GES-1 cells injury[J]. Chinese Traditional and Herbal Drugs, 2021, 52(16): 4892-4903. (in Chinese) 贺海波, 朱丽金, 贺君宇, 江伟杰, 王晓, 彭校, 陈烨韬, 宋利华, 张继红, 邹坤. 委陵菜酸对幽门螺杆菌诱导GES-1细胞损伤的保护作用[J]. 中草药, 2021, 52(16): 4892-4903. DOI:10.7501/j.issn.0253-2670.2021.16.014 |
| [89] |
LI LL, BAO B, CHAI XX, CHEN XY, SU XH, FENG SX, ZHU XH. The anti-inflammatory effect of Callicarpa nudiflora extract on H. pylori-infected GES-1 cells through the inhibition of ROS/NLRP3/caspase-1/IL-1β signaling axis[J]. The Canadian Journal of Infectious Diseases & Medical Microbiology, 2022, 2022: 5469236. |
| [90] |
LIAN DW, XU YF, REN WK, FU LJ, CHEN FJ, TANG LY, ZHUANG HL, CAO HY, HUANG P. Unraveling the novel protective effect of patchouli alcohol against Helicobacter pylori-induced gastritis: insights into the molecular mechanism in vitro and in vivo[J]. Frontiers in Pharmacology, 2018, 9: 1347. DOI:10.3389/fphar.2018.01347 |
| [91] |
TIAN J, DENG L. Study on sulforaphane suppresses NLRP3 inflammasome activation in gastric mucosa epithelial cells triggered by Helicobacter Pylori[J]. Chinese Journal of Modern Applied Pharmacy, 2021, 38(13): 1566-1571. (in Chinese) 田静, 邓莉. 萝卜硫素抑制幽门螺杆菌诱导胃黏膜上皮细胞NLRP3炎症小体活化的研究[J]. 中国现代应用药学, 2021, 38(13): 1566-1571. DOI:10.13748/j.cnki.issn1007-7693.2021.13.005 |
| [92] |
CHEN N, ZHAO CH, ZHANG TH. Selenium transformation and selenium-rich foods[J]. Food Bioscience, 2021, 40: 100875. DOI:10.1016/j.fbio.2020.100875 |
| [93] |
CHEN SY, LI YN, CHU BX, YUAN LX, LIU N, ZHU YH, WANG JF. Lactobacillus johnsonii L531 alleviates the damage caused by Salmonella typhimurium via inhibiting TLR4, NF-κB, and NLRP3 inflammasome signaling pathways[J]. Microorganisms, 2021, 9(9): 1983. DOI:10.3390/microorganisms9091983 |
| [94] |
LIU HB, ZHAN XY, XU G, WANG ZL, LI RS, WANG Y, QIN Q, SHI W, HOU XR, YANG RC, WANG J, XIAO XH, BAI ZF. Cryptotanshinone specifically suppresses NLRP3 inflammasome activation and protects against inflammasome-mediated diseases[J]. Pharmacological Research, 2021, 164: 105384. DOI:10.1016/j.phrs.2020.105384 |
| [95] |
DEO P, CHOW SH, HAN ML, SPEIR M, HUANG C, SCHITTENHELM RB, DHITAL S, EMERY J, LI J, KILE BT, VINCE JE, LAWLOR KE, NADERER T. Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation[J]. Nature Microbiology, 2020, 5(11): 1418-1427. DOI:10.1038/s41564-020-0773-2 |
| [96] |
KUMAR S, DHIMAN M. Inflammasome activation and regulation during Helicobacter pylori pathogenesis[J]. Microbial Pathogenesis, 2018, 125: 468-474. DOI:10.1016/j.micpath.2018.10.012 |
| [97] |
CONSTANTINESCU T, LUNGU CN. Anticancer activity of natural and synthetic chalcones[J]. International Journal of Molecular Sciences, 2021, 22(21): 11306. DOI:10.3390/ijms222111306 |
| [98] |
LI Q, FENG H, WANG HB, WANG YH, MOU WQ, XU G, ZHANG P, LI RS, SHI W, WANG ZL, FANG ZE, REN LT, WANG Y, LIN L, HOU XR, DAI WZ, LI ZY, WEI ZY, LIU TT, WANG JB, et al. Licochalcone B specifically inhibits the NLRP3 inflammasome by disrupting NEK7-NLRP3 interaction[J]. EMBO Reports, 2022, 23(2): e53499. DOI:10.15252/embr.202153499 |
| [99] |
KAKAR SS, PARTE S, CARTER K, JOSHUA IG, WORTH C, RAMESHWAR P, RATAJCZAK MZ. Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells[J]. Oncotarget, 2017, 8(43): 74494-74505. DOI:10.18632/oncotarget.20170 |
| [100] |
GREANEY AJ, MAIER NK, LEPPLA SH, MOAYERI M. Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism[J]. Journal of Leukocyte Biology, 2016, 99(1): 189-199. DOI:10.1189/jlb.3A0415-155RR |
| [101] |
JIANG YQ, HE L, GREEN J, BLEVINS H, GUO CQ, PATEL SH, HALQUIST MS, McRAE M, VENITZ J, WANG XY, ZHANG SJ. Discovery of second-generation NLRP3 inflammasome inhibitors: design, synthesis, and biological characterization[J]. Journal of Medicinal Chemistry, 2019, 62(21): 9718-9731. DOI:10.1021/acs.jmedchem.9b01155 |