Wuwei Kushen Changrong capsule alleviates DSS-induced colitis in mice via inhibition of NLRP3 inflammasome and STAT3 pathway
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Wuwei Kushen Changrong capsule (CompositeKeywords:
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NLRP3 is an important pattern recognition receptor in the innate immune system, and its activation induces a large number of pro-inflammatory cytokines, IL-1β and IL-18 which are involved in the development of various diseases. In recent years, it has been suggested that mitochondria are the platform for NLRP3 inflammasome activation. Additionally, exercise is considered as an important intervention strategy to mediate the innate immune responses. Generally, chronic moderate-intensity endurance training, resistance training and high-intensity interval training inhibit NLRP3 inflammasome activation in response to various pathological factors. In contrast, acute exercise activates NLRP3 inflammasome. However, the mechanisms by which exercise regulates NLRP3 inflammasome activation are largely unclear. Therefore, the mechanism of NLRP3 inflammasome activation is discussed mainly from the perspective of mitochondria in this review. Moreover, the effect and potential mechanism of exercise on NLRP3 inflammasome are explored, hoping to provide new target for relevant research.
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NLRP3 inflammasome，它由 NLRP3 (象受体 3 一样的核苷酸绑定 oligomerization 域(点头)) 组成支架， ASC (包含一张卡的联系 apoptosis 的像斑点的蛋白质) 适配器和 procaspase- 1，在 NLRP3 的细胞质的 LRR (充满白氨酸的重复) 察觉到病原体或危险信号以后，被装配。NLRP3 inflammasome 控制解朊的酶 caspase-1 的激活。Caspase-1 接着调整 proinflammasome cytokines IL-1 和 IL-18 的成熟，它导致煽动性的回答。inflammasome 戏在 Alzheimers 疾病和细菌的脑膜炎的发展的一个重要角色，和 NLRP3 inflammasome 可以为中央神经系统疾病的预防和处理成为一个新目标。
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Abstract Intracellular sensing of stress and danger signals initiates inflammatory innate immune responses by triggering inflammasome assembly, caspase-1 activation and pyroptotic cell death as well as the release of interleukin 1β (IL-1β), IL-18 and danger signals. NLRP3 broadly senses infectious patterns and sterile danger signals, resulting in the tightly coordinated and regulated assembly of the NLRP3 inflammasome, but the precise mechanisms are incompletely understood. Here, we identified NLRP11 as an essential component of the NLRP3 inflammasome in human macrophages. NLRP11 interacted with NLRP3 and ASC, and deletion of NLRP11 specifically prevented NLRP3 inflammasome activation by preventing inflammasome assembly, NLRP3 and ASC polymerization, caspase-1 activation, pyroptosis and cytokine release but did not affect other inflammasomes. Restored expression of NLRP11, but not NLRP11 lacking the PYRIN domain (PYD), restored inflammasome activation. NLRP11 was also necessary for inflammasome responses driven by NLRP3 mutations that cause cryopyrin-associated periodic syndrome (CAPS). Because NLRP11 is not expressed in mice, our observations emphasize the specific complexity of inflammasome regulation in humans.
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Abstract The NLRP3 inflammasome mediates the response to monosodium urate (MSU) crystals and is responsible for the debilitating symptoms of gout. ASC is the essential inflammasome adaptor that bridges NLRP3 to caspase-1 and inflammasome assembly is via sequential homotypic PYRIN domain (PYD)-PYD and caspase recruitment domain (CARD)-CARD interactions between NLRP3 and ASC and ASC and caspase-1, respectively. While controlled inflammasome activation is essential for host defense and wound healing, dysregulated and excessive inflammasome responses cause inflammatory diseases. Hence, proper control is key for a balanced inflammasome response. Humans, but not mice, encode a family of 3 small CARD-only proteins (COPs): CARD16, CARD17 and CARD18, but their role in controlling inflammasome responses in vivo is unknown, which is the focus of our study. COP transgenic mice show reduced MSU crystal induced release of IL-1b and consequently ameliorated gout symptoms. Transgenic macrophages and COP expressing THP-1 cells show impaired MSU crystal-mediated NLRP3 inflammasome and caspase-1 activation, cytokine release and pyroptosis, while COP KO results in a hyper response to MSU. Also, COPs show unique binding pattern to the CARD of caspase-1 and ASC in naïve, primed and MSU-activated macrophages and interfere with the essential CARD-CARD-mediated caspase-1 self interaction and the ASC-caspase-1 interaction by a competitive binding mechanism. We demonstrate that COPs are functional in mice and inhibit NLRP3 inflammasome assembly by a competitive binding mechanism that prevents cytokine release and pyroptotis and ameliorates inflammatory disease. Altogether, our findings illustrate that the COPs have a role in maintaining homeostasis. National Institutes of Health. (AI099009 and AR064349 to C.S, AI134030, AI140702 and AI120625 to C.S. and A.D.)
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Aberrant activation of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome drives the development of many complex inflammatory diseases, such as obesity, Alzheimer's disease, and atherosclerosis. However, no medications specifically targeting the NLRP3 inflammasome have become clinically available. Therefore, we aim to identify new inhibitors of the NLRP3 inflammasome in this study. Methods: Vesicle-like nanoparticles (VLNs) were extracted from garlic chives and other Allium vegetables and their effects on the NLRP3 inflammasome were evaluated in primary macrophages. After garlic chive-derived VLNs (GC-VLNs) were found to exhibit potent anti-NLRP3 inflammasome activity in cell culture, such function was further assessed in a murine acute liver injury disease model, as well as in diet-induced obesity. Finally, GC-VLNs were subjected to omics analysis to identify the active components with anti-NLRP3 inflammasome function. Results: GC-VLNs are membrane-enclosed nanoparticles containing lipids, proteins, and RNAs. They dose-dependently inhibit pathways downstream of NLRP3 inflammasome activation, including caspase-1 autocleavage, cytokine release, and pyroptotic cell death in primary macrophages. The inhibitory effects of GC-VLNs on the NLRP3 inflammasome are specific, considering their marginal impact on activation of other inflammasomes. Local administration of GC-VLNs in mice alleviates NLRP3 inflammasome-mediated inflammation in chemical-induced acute liver injury. When administered orally or intravenously, GC-VLNs accumulate in specific tissues and suppress activation of the NLRP3 inflammasome and chronic inflammation in diet-induced obese mice. The phospholipid 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) in GC-VLNs has been identified to inhibit NLRP3 inflammasome activation. Conclusions: Identification of GC-VLNs and their active component DLPC as potent inflammasome inhibitors provides new therapeutic candidates in the treatment of NLRP3 inflammasome-driven diseases.
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The nod-like receptor family pyrin domain containing 3 (NLRP3) is currently the most widely studied inflammasome and has become a hot topic of recent research. As a macromolecular complex, the NLRP3 inflammasome is activated to produce downstream factors, including caspase-1, IL-1β, and IL-18, which then promote local inflammatory responses and induce pyroptosis, leading to unfavorable effects. A growing number of studies have examined the relationship between the NLRP3 inflammasome and cardiovascular diseases (CVDs). However, some studies have shown that the NLRP3 inflammasome is not involved in the occurrence of certain diseases. Therefore, identifying the mechanism of action of the NLRP3 inflammasome and its potential involvement in the pathological process of disease progression is of utmost importance. This review discusses the mechanisms of NLRP3 inflammasome activation and the relationship between the inflammasome and CVDs, including coronary atherosclerosis, myocardial ischemia/reperfusion, cardiomyopathies and arrhythmia, as well as CVD-related treatments.
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I are multiprotein complexes inducing pro-inflammatory cytokine production in response to infection and tissue injury. The end product of inflammasome activity is caspase-1-induced release of effector molecules such as IL-1 β and IL-18 from immune cells. Despite the common outcome, the variety of triggers that initiate inflammasome activity is large, and moreover eight different inflammasome subclasses have been described. The inflammasome is a potential therapeutic target for chronic inflammatory diseases such as chronic kidney disease and atherosclerosis. To test the effects of future inflammasometargeted therapies, an ‘inflammasome bioassay’ is highly warranted. The inflammasome’s capacity to sense widely divergent ligands, and the diversity in inflammasome subclasses, indicates that a single bioassay may not be sufficient to assess potential inflammasome-modulating effects of new compounds. Therefore, we developed a set of bioassays inducing inflammasome activity, so-called ‘inflammasome challenges’. Variables that were explored included matrix/cells (whole blood, PBMCs, THP1), triggers, incubation time (3-24 hours), dose-response relationship, single trigger versus immune cell priming followed by a second trigger, and inflammasome end products (IL-1β, IL-18). We successfully developed a set of inflammasome challenges, comprising inflammasome activation by LPS alone and by different triggers after LPS priming (extracellular ATP, aluminium hydroxide, cholesterol crystals, oligomeric β-amyloid). The short-term LPS inflammasome challenge was demonstrated to be sensitive to modulation of inflammasome activity, as assessed with a direct caspase-1 inhibitor. These inflammasome challenges can be applied in translational drug development as readout measures for inflammasome inhibition, and moreover will provide mechanistic insight in regulation of inflammasome activity.
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Abstract Uric acid crystal is known to activate the NLRP3 inflammasome and to cause tissue damages, which can result in many diseases, such as gout, chronic renal injury and myocardial damage. Meanwhile, soluble uric acid (sUA), before forming crystals, is also related to these diseases. This study was carried out to investigate whether sUA could also activate NLRP3 inflammasome in cardiomyocytes and to analyse the mechanisms. The cardiomyocyte activity was monitored, along with the levels of mature IL‐1β and caspase‐1 from H9c2 cells following sUA stimulus. We found that sUA was able to activate NLRP3 inflammasome, which was responsible for H9c2 cell apoptosis induced by sUA. By elevating TLR6 levels and then activating NF‐κB/p65 signal pathway, sUA promoted NLRP3, pro‐caspase 1 and pro‐IL‐1β production and provided the first signal of NLRP3 inflammasome activation. Meanwhile, ROS production regulated by UCP2 levels also contributed to NLRP3 inflammasome assembly and subsequent caspase 1 activation and mature IL‐1β secretion. In addition, the tlr6 knockdown rats suffering from hyperuricemia showed the lower level of IL‐1β and an ameliorative cardiac function. These findings suggest that sUA activates NLRP3 inflammasome in cardiomyocytes and they may provide one therapeutic strategy for myocardial damage induced by sUA.
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Inflammasomes 是表明触发煽动性的 caspases 的激活和 interleukin-1β 的成熟的建筑群的多蛋白质；。在各种各样的 inflammasome 建筑群之中， NLRP3 inflammasome 最好被描绘并且与各种各样的人的 autoinflammatory 和自体免疫的疾病被连接了。因此， NLRP3 inflammasome 可以是为反煽动性的治疗的一个有希望的目标。在这评论，我们总结 NLRP3 inflammasome 被在 cytosol 激活的机制的当前的理解。我们也描述激活或禁止 inflammasome 汇编的 NLRP3 inflammasome 建筑群的有约束力的搭挡。我们调整 NLRP3 inflammasome 发信号的机制的知识并且这些怎么影响煽动性的回答，提供进一步的卓见进潜在的治疗学的策略治疗与 NLRP3 inflammasome 的 dysregulation 联系的煽动性的疾病。
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