NLRP3炎性小体在中枢神经系统疾病中的作用研究进展

炎症是具有血管系统的活体组织对损伤因子所发生的防御反应。神经炎症是神经系统疾病发病机制的重要组成部分,过度的神经炎症会导致神经元死亡、加剧神经系统疾病的发展,抑制神经炎症有助于神经元的存活,改善神经系统疾病的症状和预后。大量研究证实,促炎因子白介素-1β(IL-1β)、白介素-18(IL-18)和肿瘤坏死因子TNF-α在炎症反应中起关键作用。最近研究发现NLRP 3炎性小体可介导IL-1β和IL-18释放,对引发炎性反应部位的细胞焦亡至关重要。目前对神经系统疾病与炎性因子的研究较多,但对神经系统疾病与NLRP 3炎性小体之间关系的研究还在起步阶段,探明它们间的具体关系和作用将对阐明中枢神经系统疾病的发病机制和提高治疗效果具有重要意义。本文对NLRP 3炎性小体在常见神经系统疾病中的作用进行综述。     

NLRP 3炎性小体在脑缺血再灌注中的作用

NLRP3炎性小体是一种结构复杂、调控机制尚不明确的多蛋白复合体,它的过度活化涉及多个系统疾病的病理生理过程.脑缺血(CI)作为发病率最高的脑血管疾病,由于对其溶栓治疗的应用受限,因而开发CI后神经保护药物尤为重要.寻求有效的药物靶点可能为脑缺血再灌注损伤(CIRI)提供新的治疗思路.     

NLRP3炎症小体在神经血管疾病中的作用

炎症小体是多蛋白复合物,可以招募并诱导半胱氨酸天冬氨酸酶-1前体(pro-caspase-1)成为有活性的半胱氨酸天冬氨酸酶-1(caspase-1),从而促进IL-1β和IL-18成熟与释放。许多研究表明NLRP3炎症小体与缺血性脑卒中、阿兹海默症(AD)、外伤性脑损伤(TBI)、脑瘤等神经血管疾病的发生发展密切相关。本文综述了NLRP3炎症小体激活途径,并着重介绍了NLRP3炎症小体介导的在上述几种神经血管疾病中的作用,为相关研究提供了基础资料。     

NLRP3炎性小体在动脉粥样硬化中的研究进展

炎性小体是一种胞内多蛋白复合物,是固有免疫的重要组分,其中以NOD样受体蛋白3(NOD-like receptor pyrin domain containing 3,NLRP3)炎性小体最为著名。动脉粥样硬化(atherosclerosis,AS)是诱发心血管疾病的重要风险因素。在AS病情发展过程中,机体通过释放白细...     

NLRP3炎性小体在缺血再灌注损伤治疗中作用的研究进展

NLRP3 (NLRP3)炎性小体作为组成先天免疫系统的蛋白复合体,可通过调节IL-1β和IL-18的成熟释放介导炎性反应,是机体发生多种病理损伤的基础。缺血/再灌注损伤(I/RI)时产生的多种损伤因子均可激活NLRP3炎性小体,导致IL-1β和IL-18的过度释放,进而引起炎性级联反应使各组织器官的损伤加重。而抑制NLRP3炎性小体活化已成为减轻器官I/RI的有效方法。因此,探究NLRP3炎性小体介导I/RI的详细作用机制,可以为器官I/RI的防治提供理论依据。     

NLRP3炎性小体在动脉粥样硬化发生发展中的作用

NLRP3炎性小体是一种包含胞内受体(主要是NOD样受体)、半胱天冬氨酸前体和凋亡相关斑点样蛋白的蛋白质复合体.该复合体最初只是被描述为一种影响感染和炎症过程的复合体,它的活化引起半胱天冬氨酶-1的激活并剪切加工底物白细胞介素-1β(interleukin-1β,IL-1β)和白细胞介素-18(interleukin-18,IL-18),从而引起炎症反应;此外,炎性小体的激活过程对有氧糖酵解(瓦伯格效应,Warburg effect)有着重要的影响,这同样可以促进炎症的发生.随后的证据表明炎性小体的活化还影响很多代谢紊乱包括动脉粥样硬化(atherosclerosis, AS)、2型糖尿病、痛风和肥胖等.本综述将探讨AS与炎症、NLRP3炎性小体活化的关联性,以及瓦伯格效应如何关联炎症反应及炎性小体的激活.     

NLRP 3炎性小体激活调控机制及抑制剂研究新进展

含NLR家族PYRIN域蛋白3(NLRP3)炎性小体是一类细胞内多蛋白复合物,可被多种病原微生物或内源性危险分子激活,释放细胞因子IL-1β和IL-18以及引起细胞焦亡,是机体固有免疫的重要组成部分。然而其过度活化可导致慢性炎性反应,与多种重大疾病的发生发展密切相关。因此,深入探究NLRP3炎性小体激活机制对于发展其特异性抑制剂以及相关疾病的治疗具有重要意义。     

IL-27在小鼠结肠炎中的作用及对NLRP3炎性小体的影响

目的:观察白细胞介素27(IL-27)对葡聚糖硫酸钠(DSS)诱导的结肠炎小鼠结肠组织学及NOD样受体蛋白3(NLRP3)炎性小体的影响。方法:将48只雄性C57BL/6小鼠随机分为正常对照组(自由进食饮水)、DSS模型组(饮用3%DSS溶液)、低剂量IL-27组和高剂量IL-27组(在饮用DSS溶液的基础上分别腹腔注射500ng和1μg IL-27)。12 d后行疾病活动指数(DAI)及组织损伤指数(HI)评分评估炎症程度,取结肠组织行免疫组化、Western blot及qPCR检测,取血清行ELISA检测IL-1β和IL-18水平。结果:与对照组相比,模型组的DAI评分和HI评分提示小鼠的结肠炎症明显增强(P0.05),NLRP3和IL-1β的mRNA表达水平增高,NLRP3和cleaved caspase-1的蛋白水平增高,血清中IL-1β和IL-18的含量增加;与模型组相比,高剂量IL-27组的DAI评分和HI评分提示小鼠的结肠炎症明显减轻(P0.05),NLRP3和IL-1β的mRNA表达水平下降,NLRP3和cleaved caspase-1的蛋白水平降低,血清中IL-1β中和IL-18的含量也减少;与模型组比较,低剂量IL-27组除了血清中IL-1β和IL-18含量减少外,上述各项指标的差异无统计学显著性。结论:IL-27可减轻DSS结肠炎模型小鼠的炎症程度并且可抑制NLRP3炎性小体的表达和激活。     

NLRP3炎症小体研究进展

NLRP3炎症小体作为固有免疫的重要组分在机体免疫反应和疾病发生过程中具有重要作用.由于能被多种类型的病原体或危险信号所激活,NLRP3炎症小体在多种疾病过程中都发挥了关键作用,包括最初被确认的家族性周期性自身炎症反应,到2型糖尿病、阿尔海默茨病和动脉粥样硬化症等.因此,作为炎症反应的核心,NLRP3炎症小体可能为各种...     

NLRP3炎性小体激活调控机制研究新进展

NLRP3炎性小体是一种胞内多蛋白复合体,主要由NOD样受体家族成员NLRP3、接头蛋白ASC以及前体半胱天冬酶1(pro-caspase-1)组成,该炎性小体可以通过激活caspase-1促进促炎因子白细胞介素-1 beta(IL-1β)和IL-18的分泌以及细胞焦亡(pyroptosis)的形成.NLRP3炎性小体的激活在很多自身免疫性及自身炎症性疾病中扮演着重要的角色,因此,深入探究NLRP3炎性小体激活的调控机制可为NLRP3炎性小体相关疾病的治疗提供更多新的思路.     

Functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes during infection-mediated inflammation

Inflammation is a part of the body's immune response for protection against pathogenic infections and other cellular damages; however, chronic inflammation is a major cause of various diseases. One key step in the inflammatory response is the activation of inflammasomes, intracellular protein complexes comprising pattern recognition receptors and other inflammatory molecules. The role of the NLRP3 inflammasome in inflammatory responses has been extensively investigated; however, the caspase-11 inflammasome has been recently identified and has been classified as a ‘non-canonical’ inflammasome, and emerging studies have highlighted its role in inflammatory responses. Because the ligands and the mechanisms for the activation of these two inflammasomes are different, studies to date have separately described their roles, although recent studies have reported the functional cooperation between these two inflammasomes during an inflammatory response. This review discusses the studies investigating the functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes in the context of inflammatory responses; moreover, it provides insight for the development of novel anti-inflammatory therapeutics to prevent and treat infectious and inflammatory diseases.     

Posttranslational modifications of NLRP3 and their regulatory roles in inflammasome activation

The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is a multimolecular complex that plays a fundamental role in inflammation. Optimal activation of NLRP3 inflammasome is crucial for host defense against pathogens and the maintenance of immune homeostasis. Aberrant NLRP3 inflammasome activity has been implicated in various inflammatory diseases. Posttranslational modifications (PTMs) of NLRP3, a key inflammasome sensor, play critical roles in directing inflammasome activation and controlling the severity of inflammation and inflammatory diseases, such as arthritis, peritonitis, inflammatory bowel disease, atherosclerosis, and Parkinson's disease. Various NLRP3 PTMs, including phosphorylation, ubiquitination, and SUMOylation, could direct inflammasome activation and control inflammation severity by affecting the protein stability, ATPase activity, subcellular localization, and oligomerization of NLRP3 as well as the association between NLRP3 and other inflammasome components. Here, we provide an overview of the PTMs of NLRP3 and their roles in controlling inflammation and summarize potential anti-inflammatory drugs targeting NLRP3 PTMs.     

Reconciling protective and pathogenic roles of the NLRP3 inflammasome in leishmaniasis

Leishmaniasis is a global health problem that affects more than 2 billion people worldwide. Recent advances in research have demonstrated critical roles for cytoplasmic sensors and inflammasomes during Leishmania spp. infection and pathogenesis. Specifically, several studies have focused on the role of nod-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome and inflammasome-associated cytokines IL-1β and IL-18 in leishmaniasis. Despite these studies, our understanding of the priming and activation events that lead to NLRP3 inflammasome activation during Leishmania spp. infection is limited. Furthermore, whether NLRP3 plays a protective or pathogenic role during Leishmania spp. infection is far from resolved, with some studies showing a protective role and others showing a pathogenic role. In this review, we performed a critical review of the literature to provide a current update on priming and activating signals required for NLRP3 inflammasome activation during Leishmania spp. infection. Finally, we provide a thorough review of the literature to reconcile differences in the observed protective vs pathogenic roles of the NLRP3 inflammasome during Leishmania spp. infection.     

Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases

Neuroinflammation is considered as a detrimental factor in neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), etc. Nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3), the most well-studied inflammasome, is abundantly expressed in microglia and has gained considerable attention. Misfolded proteins are characterized as the common hallmarks of neurodegenerative diseases due to not only their induced neuronal toxicity but also their effects in over-activating microglia and the NLRP3 inflammasome. The activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Emerging evidence indicates that microglial autophagy plays an important role in the maintenance of brain homeostasis and the negative regulation of NLRP3 inflammasome-mediated neuroinflammation. The excessive activation of NLRP3 inflammasome impairs microglial autophagy and further aggravates the pathogenesis of neurodegenerative diseases. In this review article, we summarize and discuss the NLRP3 inflammasome and its specific inhibitors in microglia. The crucial role of microglial autophagy and its inducers in the removal of misfolded proteins, the clearance of damaged mitochondria and reactive oxygen species (ROS), and the degradation of the NLRP3 inflammasome or its components in neurodegenerative diseases are summarized. Understanding the underlying mechanisms behind the sex differences in NLRP3 inflammasome-mediated neurodegenerative diseases will help researchers to develop more targeted therapies and increase our diagnostic and prognostic abilities. In addition, the superiority of the combined use of microglial autophagy inducers with the specific inhibitors of the NLRP3 inflammasome in the inhibition of NLRP3 inflammasome-mediated neuroinflammation requires further preclinical and clinical validations in the future.     

RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor

The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory, metabolic and neurodegenerative diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials, but its effects on inflammatory diseases are not known. Here, we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory diseases. RRx-001 inhibits the activation of the canonical, noncanonical, and alternative NLRP3 inflammasomes but not the AIM2, NLRC4 or Pyrin inflammasomes. Mechanistically, RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction, which is critical for the assembly and activation of the NLRP3 inflammasome. More importantly, RRx-001 treatment attenuates the symptoms of lipopolysaccharide (LPS)-induced systemic inflammation, dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.     

NLRP3炎症小体激活的调控机制研究进展

NLRP3炎症小体是固有免疫系统的重要组成部分,在抵抗病原体感染及危险信号刺激过程中发挥关键作用。同时,NLRP3炎症小体的异常激活也与糖尿病、阿尔茨海默病、红斑狼疮等疾病密切相关。因此,调控和干预炎症小体激活过程对维持机体免疫稳态和发挥免疫功能有重要作用。本文从NLRP3的翻译后修饰、互作分子、细胞器和细胞定位改变以及与NLRP3功能相关的代谢过程和代谢物等多个方面综述了NLRP3炎症小体激活的调控机制研究进展,以期为理解炎症小体激活和炎症反应的发生,以及治疗炎症相关疾病提供新的借鉴。     

NLRP3炎症小体与溃疡性结肠炎的研究进展

溃疡性结肠炎是肠道慢性炎性反应性疾病,遗传易感性、肠道菌群和黏膜免疫功能失调在溃疡性结肠炎的发生发展过程中起重要作用.目前研究显示NLRP3基因与溃疡性结肠炎的易感性相关,NLRP3炎症小体可维持肠道内环境稳定,对实验性结肠炎具有保护作用,其功能缺陷可能导致对溃疡性结肠炎易感.NLRP3炎症小体有可能成为溃疡性结肠炎治疗的新靶点.