炎性小体激活与细胞焦亡的研究进展

细胞焦亡是一种依赖天冬氨酸特异性半胱氨酸蛋白酶1(cysteinyl aspartate specific proteinase 1,caspase-1)/caspase-11的程序性细胞死亡方式。炎性小体的激活在细胞焦亡过程中扮演重要角色。当病原体入侵时,核苷酸结合寡聚化结构域样受体(nucleotide-binding oligomerization domain-like receptor,NLR)和黑色素瘤缺乏因子2(absent in melanoma 2,AIM2)等胞内模式识别受体(pattern recognition receptor,PRR)与相应配体结合,导致炎性小体多蛋白复合物组装和caspase-1/caspase-11激活,进而诱导细胞焦亡发生。深入研究炎性小体激活和细胞焦亡的相关机制,对认识炎症性疾病的发生发展非常重要。本文就炎性小体激活与细胞焦亡的研究进展进行综述。     

炎症小体调控机制的研究进展

炎症小体(Inflammasome)是一种由机体胞浆内模式识别受体(PRRs)参与组成的多蛋白复合体,主要参与天然免疫反应中caspase-1激活,并介导IL-1β、IL-18的前体产生成熟细胞因子以及诱导细胞凋亡。NLRP3、NLRC4、NLRP1、AIM2是目前研究较多的炎症小体,对其结构、组成成分、作用机制等方面已有较为深入的研究,而主要只对炎症小体的活化及负性调控机制的研究进展进行了综述。     

AIM2炎症小体介导细胞焦亡的研究进展

细胞焦亡是一种程序性细胞死亡，参与了多种疾病的发生发展，而炎症反应在细胞焦亡中的作用是目前的研究热点。炎症小体是炎症反应的重要组成部分，其中黑色素瘤缺乏因子2 (absent in melanoma 2,AIM2)炎症小体的激活是诱发由含半胱氨酸的天冬氨酸蛋白酶1 (caspase-1)介导的细胞焦亡的重要因素。靶向AIM2炎症小体激活与细胞焦亡可作为临床相关疾病治疗的有效策略，本文综述了AIM2炎症小体介导的细胞焦亡的研究进展。     

病原体与宿主炎症小体相互作用

炎症小体(Inflammasome)是细胞质中多种蛋白组装成的复合物,炎症小体的激活能活化半胱天冬酶-1(caspase-1),进而引起系列促炎细胞因子的成熟与分泌和诱导细胞焦亡。当病原体感染时,炎症小体的激活在宿主天然免疫应答中起重要作用。大量研究表明,多数情况下炎症小体对宿主起保护作用,仅少数情况下保护作用不明显或表现出有利于病原体生存的一面。在长期进化中,病原体也发展出逃避宿主炎症小体作用的策略。病原体可直接抑制炎症小体的激活或减弱炎症小体的作用。本文从病原体感染宿主中炎症小体的作用及病原体对宿主炎性症小体的逃避机制两方面对二者相互作用的最新研究进展进行综述。     

牛病毒性腹泻病毒Erns蛋白激活NOD样受体热蛋白结构域相关蛋白3炎症小体诱发细胞焦亡的研究

【目的】牛病毒性腹泻病毒(bovine viral diarrhea virus, BVDV)是引起牛病毒性腹泻-黏膜病的关键病毒。BVDV的结构蛋白Erns可在病毒感染的初期削弱宿主的免疫防御,引发牛群炎症反应。核苷酸寡聚化结构域样受体(nucleotide-binding oligomerization domain, NOD)热蛋白结构域相关蛋白3 (NLRP3)炎症小体是NOD样受体(NOD-like receptor, NLRs)家族重要成员,调控炎症性疾病的发生发展,同时激活的NLRP3炎症小体能够引起宿主细胞焦亡,进而诱发级联放大的炎症反应。但BVDV Erns蛋白在BVDV感染诱发炎症反应的分子机制尚不清楚。【方法】为进一步探索Erns蛋白对BVDV感染激活NLRP3炎症小体诱发细胞焦亡的影响,构建了BVDV Erns蛋白的真核表达质粒pCMV-HA-Erns,过表达BVDV Erns蛋白,检测BVDV感染细胞中NLRP3炎症小体组分[半胱氨酸蛋白酶(caspase-1)、凋亡相关斑点样蛋白(apoptosis-associated speck-like protein, ASC)和NLRP3]、IL-1β的mRNA转录水平和蛋白表达水平,以及细胞死亡调节蛋白(gasdermin D, GSDMD)的基因表达和蛋白剪切情况,并通过扫描电镜观察牛睾丸(bovine testis, BT)细胞膜成孔及BT细胞内容物释放情况,以分析Erns蛋白诱导BT细胞产生细胞焦亡。【结果】Erns蛋白能够显著引起NLRP3炎症小体活化进而激活caspase-1,活化的caspase-1一方面切割GSDMD,形成有活性的GSDMD-N端并在BT细胞膜形成孔洞,释放内容物,诱导BT细胞发生细胞焦亡;另一方面活化的caspase-1切割pro-IL-1β,形成有活性的IL-1β,并释放到BT细胞外,引起BT细胞上清中IL-1β水平上升。【结论】系统解析了BVDV Erns蛋白激活NLRP3炎症小体介导细胞焦亡的产生,对疫苗及治疗药物的研制具有重要指导意义。     

NLRP3炎症小体与2型糖尿病的研究进展

NLRP3炎症小体作为固有免疫系统的重要组成部分,在2型糖尿病的发病过程中起着重要作用,而白细胞介素1β(IL-1β)是介导其发挥作用的关键因子。核糖体蛋白质合成、嘌呤受体P2X7、活性氧敏感的硫氧还原蛋白相互作用蛋白(TXNIP)与NLRP3炎症小体激活密切相关。肥胖时胰岛素作用的靶组织中NLRP3、IL-1β表达均增高,其介导的炎症反应在胰岛β细胞功能障碍、凋亡以及胰岛素抵抗发生过程中起关键作用。NLRP3炎症小体被多种途径激活,从而上调胰岛和脂肪组织中IL-1β的表达,促进胰岛β细胞凋亡及胰岛素抵抗的发生发展,导致糖尿病的产生。     

病毒感染激活和抑制炎症小体的研究进展

促炎细胞因子白细胞介素1β(IL-1β)和白细胞介素18(IL-18)主要由巨噬细胞和树突细胞产生,是宿主针对各种侵入病原体产生先天免疫应答的重要介质。这些促炎细胞因子从病毒感染的细胞中分泌,被称为炎症小体的多蛋白复合物严格调控。根据炎症小体识别蛋白的种类,炎症小体主要分为两类,即核苷酸结合寡聚结构域样受体(NOD-like receptors,NLRs)和黑色素瘤缺乏因子2样受体(Absent in melanoma 2,AIM2)炎症小体。与其他宿主防御机制不同,炎症小体活化后,会诱导促炎细胞因子IL-1β、IL-18的成熟及分泌。适量的促炎细胞因子有利于控制病理性感染,但如果过量,则会对机体造成一定免疫损伤。本文主要对近几年有关病毒感染对炎症小体的激活和抑制机制进行了综述,总结分析了炎症小体在参与天然免疫反应及病毒感染致病过程中具有的重要作用。     

NLRP3炎症小体与自身免疫性疾病的相关性研究进展

炎症小体是存在于细胞内由激活自身免疫应答的多种蛋白质组成的复合体,可诱导半胱天冬蛋白酶(caspase)-1自我剪切,caspase-1能够调控白细胞介素(IL)-1β、IL-18的产生,并进而刺激炎症小体的形成和分泌,调控机体的自身免疫应答反应。NLRP3炎症小体属于NOD样受体家族,是一种胞内模式识别受体,主要存在于巨噬细胞和树突状细胞,发挥激活机体免疫炎症的关键作用。病原相关分子模式及损伤相关分子模式与NLRPs结合,启动固有免疫应答,从而导致自身免疫性疾病的发生和发展。本文通过分析归纳近年来炎症小体与自身免疫性疾病的相关性的研究进展,以期为以炎症小体为作用靶点,防治自身免疫性疾病的研究提供指导。     

炎性小体在诱导脊髓损伤神经炎症中的作用

脊髓损伤的治疗与康复一直是医学领域的重大难题,尤其是在改善损伤的神经功能方面进展甚微。继发性损伤是造成脊髓损伤后神经功能障碍的主要原因,炎症反应是继发性损伤阶段最重要的病理过程。急性期通过抑制神经炎症来减轻继发性损伤被认为可减轻神经功能损害而达到神经保护作用。炎性小体是一类蛋白质复合体,由模式识别受体中的NLRs家族和PHYIN家族的受体蛋白质作为主要框架组装并命名,常见的炎性小体包括NLRP1、NLRP3、NLRC4(IPAF)、AIM2等。在感染或受到损伤刺激时,炎性小体在细胞质内组装,并激活促炎症蛋白酶胱天蛋白酶1(caspase-1),活化的胱天蛋白酶1一方面促进促炎症细胞因子IL-1β和IL-18的前体成熟和分泌,另一方面介导细胞焦亡。细胞焦亡以细胞肿胀破裂并释放细胞内容物为特征,是在炎症和应激的病理条件下诱导的程序性细胞死亡方式。促炎症细胞因子和焦亡释放的胞内物质都可作为促炎信号引发炎症反应。近期发现,炎性小体通过诱导促炎因子释放以及介导细胞焦亡等途径, 参与激活脊髓损伤后的炎症级联反应,加重继发性神经炎症。靶向抑制炎性小体的激活可减轻炎症反应,促进神经细胞存活,达到神经保护作用。因此,炎性小体有望成为脊髓损伤治疗的新靶点。本文拟从炎性小体的结构及其在脊髓损伤中的作用、激活机制和治疗前景进行综述,以期为后续研究提供思路。     

自噬与NLRP3炎症小体激活间的相互作用

自噬作为真核生物细胞遭遇各种应激压力时发生的一种基本应答方式,参与细胞的多种生命活动,使细胞在各种应激条件下维持一种动态平衡状态。NOD样受体家族核苷酸结合寡聚化结构域样受体3（NOD-like receptor family,pyrin domain containing 3,NLRP3）炎症小体,是生物体内防御病原微生物的固有免疫防御系统的重要组成部分。NLRP3炎症小体通过激活胱天蛋白酶-1（caspase-1）,从而促进白细胞介素-1β（interleukin-1,IL-1β）和白细胞介素-18（interleukin-18,IL-18）等促炎细胞因子的成熟和分泌,继而介导炎症的发生。众多研究表明,自噬能够负向或正向调控NLRP3炎症小体的激活。同时,NLRP3炎症小体也会逆向影响自噬的作用。本文对自噬包括选择性自噬与NLRP3炎症小体激活的相互作用,以及通过激活自噬抑制NLRP3炎症小体,从而在炎症相关疾病治疗中的应用进行综述。     

Inflammatory caspases and inflammasomes: master switches of inflammation

Fifteen years have passed since the cloning and characterization of the interleukin-1beta-converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction.     

Formation of noncanonical high molecular weight caspase-3 and -6 complexes and activation of caspase-12 during serum starvation induced apoptosis in AKR-2B mouse fibroblasts

Apoptosis is mainly brought about by the activation of caspases, a protease family with unique substrate selectivity. In mammals, different complexes like the DISC complex or the apoptosome complexes have been delineated leading to the cleavage and thus activation of the executioner caspases. Although caspase-3 is the main executioner caspase in apoptosis induced by serum starvation in AKR-2B fibroblasts as demonstrated by affinity labeling with YVK(-bio)D.aomk and partial purification of cytosolic extracts by high performance ion exchange chromatography, its activation is apparently caused by a noncanonical pathway: (1) Expression of CrmA, an inhibitor of caspase-8, failed to suppress apoptosis; (2) There was no formation of high molecular weight complexes of Apaf-1 indicative for its activation. Furthermore no cleavage of caspase-9 was observed. But surprisingly, gelfiltration experiments revealed the distribution of caspase-3 and -6 into differently sized high molecular weight complexes during apoptosis. Though the apparent molecular weights of the complexes containing caspase-3 (600 kD for apoptosome and 250 kD for microapoptosome) are in accordance with recently published data, the activity profiles differ strikingly. In AKR-2B cells caspase-3 is mainly recovered as uncomplexed enzyme and in much lower levels in the apoptosomes. Remarkably, the 600 kD and 250 kD complexes containing activated caspase-3 were devoid of Apaf-1 and cytochrome c. In addition a new 450 kD complex containing activated caspase-6 was found that is clearly separated from the caspase-3 containing complexes. Furthermore, we disclose for the first time the activation of caspase-12 in response to serum starvation. Activated caspase-12 is detectable as non-complexed free enzyme in the cytosol.     

Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes

The Apaf-1 apoptosome is a multi-subunit caspase-activating scaffold that is assembled in response to diverse forms of cellular stress that culminate in apoptosis. To date, most studies on apoptosome composition and function have used apoptosomes reassembled from recombinant or purified proteins. Thus, the precise composition of native apoptosomes remains unresolved. Here, we have used a one-step immunopurification approach to isolate catalytically active Apaf-1/caspase-9 apoptosomes, and have identified the major constituents of these complexes using mass spectrometry methods. Using this approach, we have also assessed the ability of putative apoptosome regulatory proteins, such as Smac/DIABLO and PHAPI, to regulate the activity of native apoptosomes. We show that Apaf-1, caspase-9, caspase-3 and XIAP are the major constituents of native apoptosomes and that cytochrome c is not stably associated with the active complex. We also demonstrate that the IAP-neutralizing protein Smac/DIABLO and the tumor-suppressor protein PHAPI can enhance the catalytic activity of apoptosome complexes in distinct ways. Surprisingly, PHAPI also enhanced the activity of purified caspase-3, suggesting that it may act as a co-factor for this protease.     

Apoptosome: a platform for the activation of initiator caspases

Apoptosome refers to the adaptor protein complex that mediates the activation of an initiator caspase at the onset of apoptosis. In mammalian cells, caspase-9, caspase-8, and caspase-2 rely on the apoptotic protease-activating factor 1 (Apaf-1)-apoptosome, death-inducing signaling complex (DISC), and PIDDosome, respectively, for activation. In Drosophila, activation of the caspase-9 homolog Dronc requires assembly of an apoptosome comprised of Dark/Hac-1/Dapaf-1. In Caenorhabditis elegans, activation of the caspase CED-3 is facilitated by the CED-4-apoptosome. Recent biochemical and structural investigation revealed significant insights into the assembly and function of the various apoptosomes. Nonetheless, conclusive mechanisms by which the initiator caspases are activated by the apoptosomes remain elusive. Several models have been proposed to explain the activation process. The induced proximity model summarizes the general process of initiator caspase activation. The proximity-driven dimerization model describes how initiator caspases respond to induced proximity and offers an explanation for their activation. Regardless of how initiator caspases are activated, enhanced activity must be correlated with altered active site conformation. The induced conformation model posits that the activated conformation for the active site of a given initiator caspase is attained through direct interaction with the apoptosome or through homo-oligomerization facilitated by the apoptosome.     

Sunburned skin activates inflammasomes

Ultraviolet (UV) irradiation injures the epidermis, resulting in sunburn and inflammation. UV-irradiated keratinocytes secrete interleukin-1beta through a caspase-1-dependent mechanism. In seeking a link between UV-irradiation and caspase-1 activation, a prominent role for the NOD-like receptor (NLR) family of innate immunity proteins was discovered recently. NLRs activate caspases through the assembly of macromolecular complexes called 'inflammasomes.' Although the mechanism by which UV-irradiation activates inflammasomes remains obscure, these recent findings shed light on NLRs as intermediaries between cell injury and inflammation.     

Caspase-1 Is an Apical Caspase Leading to Caspase-3 Cleavage in the AIM2 Inflammasome Response,Independent of Caspase-8

Canonical inflammasomes are multiprotein complexes that can activate both caspase-1 and caspase-8. Caspase-1 drives rapid lysis of cells by pyroptosis and maturation of interleukin (IL)-1β and IL-18. In caspase-1-deficient cells, inflammasome formation still leads to caspase-3 activation and slower apoptotic death, dependent on caspase-8 as an apical caspase. A role for caspase-8 directly upstream of caspase-1 has also been suggested, but here we show that caspase-8-deficient macrophages have no defect in AIM2 inflammasome-mediated caspase-1 activation, pyroptosis, and IL-1β cleavage. In investigating the inflammasome-induced apoptotic pathway, we previously demonstrated that activated caspase-8 is essential for caspase-3 cleavage and apoptosis in caspase-1-deficient cells. However, here we found that AIM2 inflammasome-initiated caspase-3 cleavage was maintained in Ripk3^?/? Casp8^?/? macrophages. Gene knockdown showed that caspase-1 was required for the caspase-3 cleavage. Thus inflammasomes activate a network of caspases that can promote both pyroptotic and apoptotic cell death. In cells where rapid pyroptosis is blocked, delayed inflammasome-dependent cell death could still occur due to both caspase-1- and caspase-8-dependent apoptosis. Initiation of redundant cell death pathways is likely to be a strategy for coping with pathogen interference in death processes.     

Single-cell imaging of inflammatory caspase dimerization reveals differential recruitment to inflammasomes

The human inflammatory caspases, including caspase-1, -4, -5 and -12, are considered as key regulators of innate immunity protecting from sepsis and numerous inflammatory diseases. Caspase-1 is activated by proximity-induced dimerization following recruitment to inflammasomes but the roles of the remaining inflammatory caspases in inflammasome assembly are unclear. Here, we use caspase bimolecular fluorescence complementation to visualize the assembly of inflammasomes and dimerization of inflammatory caspases in single cells. We observed caspase-1 dimerization induced by the coexpression of a range of inflammasome proteins and by lipospolysaccharide (LPS) treatment in primary macrophages. Caspase-4 and -5 were only dimerized by select inflammasome proteins, whereas caspase-12 dimerization was not detected by any investigated treatment. Strikingly, we determined that certain inflammasome proteins could induce heterodimerization of caspase-1 with caspase-4 or -5. Caspase-5 homodimerization and caspase-1/-5 heterodimerization was also detected in LPS-primed primary macrophages in response to cholera toxin subunit B. The subcellular localization and organization of the inflammasome complexes varied markedly depending on the upstream trigger and on which caspase or combination of caspases were recruited. Three-dimensional imaging of the ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain)/caspase-1 complexes revealed a large spherical complex of ASC with caspase-1 dimerized on the outer surface. In contrast, NALP1 (NACHT leucine-rich repeat protein 1)/caspase-1 complexes formed large filamentous structures. These results argue that caspase-1, -4 or -5 can be recruited to inflammasomes under specific circumstances, often leading to distinctly organized and localized complexes that may impact the functions of these proteases.Correct assembly and regulation of inflammasomes is critical for mediating inflammation and preventing uncontrolled inflammation under infectious and sterile conditions. These supramolecular structures converge on the activation of caspase-1. Upon activation, caspase-1 cleaves the proinflammatory cytokines interleukin1β (IL-1β) and IL-18 to their active mature forms,^{1, 2} which are then released from the cell to direct the immediate removal of pathogens.Caspase-1 is activated by proximity-induced dimerization upon recruitment to inflammasomes, which are multiprotein signaling complexes that act as activation platforms.³ Many distinct inflammasomes exist, and each inflammasome includes a sensor protein (e.g., NALP1 (NACHT leucine-rich repeat protein 1)/NLRP1 (NOD-like receptor protein 1), NALP3/NLRP3, AIM2 (absent in melanoma 2) or IPAF (ICE protease-activating factor)/NLRC4 (NLR family CARD domain-containing protein 4)), which is activated by specific proinflammatory molecules. These include pathogen-derived stimuli, known as pathogen-associated molecular patterns (PAMPs), or non-pathogenic inflammatory stimuli, known as damage-associated molecular patterns.⁴ Inflammasome assembly is governed by a series of homotypic interactions, which are mediated by specific protein:protein interaction domains, such as the pyrin domain (PYD) and the caspase recruitment domain (CARD).^{5, 6} For example, NALP1 and NALP3 both contain a PYD at their C terminus that binds to the PYD in the adaptor protein, ASC (apoptosis-associated speck-like protein containing a CARD).^{7, 8} ASC also contains a CARD,⁹ which binds to the CARD in the prodomain of caspase-1 (C1-Pro), resulting in caspase-1 dimerization and activation.¹⁰ Inflammasomes can also be ASC-independent, such as IPAF, which interacts directly with caspase-1.¹¹ Interestingly, ASC can enhance IPAF-induced caspase-1 activation,^{12, 13} which indicates that more complex interactions between these proteins may exist.Caspase-1 is one of the inflammatory caspases, including the human caspases (caspase-1, -4, -5 and -12) and murine caspase-11.¹⁴ The roles of caspase-4, -5, and -12 in caspase-1 activation and inflammasome pathways are not clear. Full-length caspase-12, which is only expressed by ~20% of people of African descent, can inhibit caspase-1 activity.¹⁵ Most of all human populations express the short form of caspase-12 (caspase-12 S or C12S), which arose from a point mutation leading to a premature stop codon just after the prodomain. This truncated form of caspase-12 is associated with increased resistance to sepsis,¹⁵ indicating that caspase-12 has an important role in inflammation. Caspase-11 mediates caspase-1 activation in response to Escherichia coli and Citrobacter rodentium in mice.¹⁶ Caspase-11 also triggers an inflammatory form of cell death, known as pyroptosis, independent of caspase-1, ASC and NALP3. This is known as the noncanonical inflammasome pathway.¹⁶ Humans do not express caspase-11 and express caspase-4 and -5 instead. Recent evidence indicates that caspase-4 and -5 act as direct intracellular sensors for lipopolysaccharide (LPS) to induce pyroptosis, independent of any additional inflammasome proteins.¹⁷ However, this does not rule out the possibility that caspase-4 and -5 can be recruited to inflammasomes under certain circumstances.The inflammatory caspases are considered to be initiator caspases, based on structural similarities between them and caspase-2, -8 and -9.¹⁸ We previously reported the use of caspase bimolecular fluorescence complementation (BiFC) to measure induced proximity of the initiator caspase, caspase-2.¹⁹ We adapted BiFC, where non-fluorescent fragments of the yellow fluorescent protein, Venus (‘split Venus''), can associate to reform the fluorescent complex when fused to interacting proteins. When caspase-2 was fused to each half of split Venus, the recruitment of caspase-2 to its activation platform and the subsequent induced proximity resulted in association of the two Venus halves. This resulted in an increase in fluorescence that represents caspase dimerization. Our caspase BiFC method facilitates specific analysis of caspase interactions at the level of the activation platform. Importantly, caspase BiFC can reveal the structural organization and localization of activation platforms in living cells.Here, we extend the caspase BiFC approach to interrogate the inflammatory caspases. We show that there are considerable differences in the organization and distribution of different inflammasomes depending on the upstream signals and on which inflammatory caspase is recruited. Our studies reveal unexpected heterodimerization interactions between caspase-1 and additional inflammatory caspases, presenting a new outcome of inflammasome assembly.     

Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity

Bacterial sensing by intracellular Nod proteins and other Nod-like receptors (NLRs) activates signaling pathways that mediate inflammation and pathogen clearance. Nod1 and Nod2 associate with the kinase Rip2 to stimulate NF-kappaB signaling. Other cytosolic NLRs assemble caspase-1-activating multiprotein complexes termed inflammasomes. Caspase-12 modulates the caspase-1 inflammasome, but unlike other NLRs, Nod1 and Nod2 have not been linked to caspases, and mechanisms regulating the Nod-Rip2 complex are less clear. We report that caspase-12 dampens mucosal immunity to bacterial infection independent of its effects on caspase-1. Caspase-12 deficiency enhances production of antimicrobial peptides, cytokines, and chemokines to entric pathogens, an effect dependent on bacterial type III secretion and the Nod pathway. Mechanistically, caspase-12 binds to Rip2, displacing Traf6 from the signaling complex, inhibiting its ubiquitin ligase activity, and blunting NF-kappaB activation. Nod activation and resulting antimicrobial peptide production constitute an early innate defense mechanism, and caspase-12 inhibits this mucosal antimicrobial response.     

炎症小体在对抗微生物感染中的作用

炎症小体(inflammasomes)是由胞浆内模式识别受体(PRRs)参与组装的多蛋白复合物,是天然免疫系统的重要组成部分。炎症小体能够识别病原相关分子模式(PAMPs)或者宿主来源的危险信号分子(DAMPs),招募和激活促炎症蛋白酶Caspase-1。活化的Caspase-1切割IL-1β和IL-18的前体,产生相应的成熟细胞因子。炎症小体的活化还能够诱导细胞的炎症坏死(pyroptosis)。目前已经确定多种炎症小体参与了针对多种病原体的宿主防御反应,病原体也已经进化出多种相应的机制来抑制炎症小体的活化。该文总结了炎症小体在抗感染免疫研究领域的最新进展,重点讨论了炎症小体对细菌、病毒、真菌和寄生虫的识别,以及炎症小体的活化在宿主抗感染过程中所发挥的作用。     

Caspase-7: A protease involved in apoptosis and inflammation

Caspase-7 was considered to be redundant with caspase-3 because these related cysteine proteases share an optimal peptide recognition sequence and have several endogenous protein substrates in common. In addition, both caspases are proteolytically activated by the initiator caspase-8 and -9 during death receptor- and DNA-damage-induced apoptosis, respectively. However, a growing body of biochemical and physiological data indicate that caspase-7 also differs in significant ways from caspase-3. For instance, several substrates are specifically cleaved by caspase-7, but not caspase-3. Moreover, caspase-7 activation requires caspase-1 inflammasomes under inflammatory conditions, while caspase-3 processing proceeds independently of caspase-1. Finally, caspase-7 deficient mice are resistant to endotoxemia, whereas caspase-3 knockout mice are susceptible. These findings suggest that specifically interfering with caspase-7 activation may hold therapeutic value for the treatment of cancer and inflammatory ailments.