Members of the nucleotide-binding domain and leucine-rich repeat (LRR)-containing (NLR) family and the pyrin and HIN domain (PYHIN) family can form multiprotein complexes termed ‘inflammasomes’. The ...biochemical function of inflammasomes is to activate caspase-1, which leads to the maturation of interleukin 1 beta (IL-1β) and IL-18 and the induction of pyroptosis, a form of cell death. Unlike other inflammasomes, the NLRP3 inflammasome can be activated by diverse stimuli. The importance of the NLRP3 inflammasome in immunity and human diseases has been well documented, but the mechanism and regulation of its activation remain unclear. In this review we summarize current understanding of the mechanism and regulation of NLRP3 inflammasome activation as well as recent advances in the noncanonical and alternative inflammasome pathways.
The NLRP3 inflammasome is an essential mediator of host immune responses through the activation of caspase-1 and interleukin 1 beta (IL-1β)/IL-18.
The NLRP3 inflammasome is thought to sense the disturbance of cellular homeostasis rather than directly recognizing a common motif present in its activators, and multiple cellular signals have been proposed to trigger its activation, including K+ efflux, Ca2+ signaling, mitochondrial dysfunction, and lysosomal rupture.
Noncanonical and alternative inflammasome pathways were recently shown to activate the NLRP3 inflammasome.
Nek7 has emerged as an essential regulator of NLRP3 inflammasome activation.
Alzheimer's disease is the most common form of progressive dementia, typified initially by short term memory deficits which develop into a dramatic global cognitive decline. The classical hall marks ...of Alzheimer's disease include the accumulation of amyloid oligomers and fibrils, and the intracellular formation of neurofibrillary tangles of hyperphosphorylated tau. It is now clear that inflammation also plays a central role in the pathogenesis of the disease through a number of neurotoxic mechanisms. Microglia are the key immune regulators of the CNS which detect amyloidopathy through cell surface and cytosolic pattern recognition receptors (PRRs) and respond by initiating inflammation through the secretion of cytokines such as interleukin‐1β (IL‐1β). Inflammasomes, which regulate IL‐1β release, are formed following activation of cytosolic PRRs, and using genetic and pharmacological approaches, NLRP3 and NLRP1 inflammasomes have been found to be integral in pathogenic neuroinflammation in animal models of Alzheimer's disease. Therefore, the inflammasomes are very promising novel pharmacological targets which merit further research in the continued endeavor for efficacious therapeutics for Alzheimer's disease.
The inflammasome complex is part of the innate immune system, which serves to protect the host against harm from pathogens and damaged cells. It is a term first proposed by Tschopp's group in 2002, ...with numerous original research articles and reviews published on the topic since. There have been many types of inflammasome identified, but all result in the common pathway of activation of caspases and interleukin 1β along with possible cell death called pyroptosis. Despite a growing body of research investigating the structure and function of the inflammasome in animal models, there is still limited evidence identifying inflammasome components in human physiology and disease. In this review, we explore the molecular structure and mechanism of activation of the inflammasome with a particular focus on inflammasome complexes expressed in humans. Inflammasome components have been identified in several human peripheral and brain tissues using both in vivo and ex vivo work, and the inflammasome complex has been shown to be associated with several genetic and acquired inflammatory and neoplastic disorders. We discuss the strengths and weaknesses of the information available on the inflammasome with an emphasis on the importance of prioritizing work on human tissue. There is a huge demand for more effective treatments for a number of inflammatory and neurodegenerative diseases. Modulation of the inflammasome has been proposed as a novel treatment for several of these diseases and there are currently clinical trials ongoing to test this theory.
Inflammasome activation culminates in activation of caspase‐1, which leads to the maturation and subsequent release of cytokines of the interleukin 1 (IL‐1) family and results in a particular form of ...cell death known as pyroptosis. In addition, in the murine system, a so‐called non‐canonical inflammasome involving caspase‐11 has been described that directly responds to cytosolic LPS. Here, we show that the human monocytic cell line THP1 activates the inflammasome in response to cytosolic LPS in a TLR4‐independent fashion. This response is mediated by caspase‐4 and accompanied by caspase‐1 activation, pyroptosis, and IL‐1β maturation. In addition to caspase‐4, efficient IL‐1β conversion upon intracellular LPS delivery relies on potassium efflux, NLRP3, ASC, and caspase‐1, indicating that although caspase‐4 activation alone is sufficient to induce pyroptosis, this process depends on the NLRP3 inflammasome activation to drive IL‐1β maturation. Altogether, this study provides evidence for the presence of a non‐canonical inflammasome in humans and its dependence on caspase‐4.
Pyroptosis is a caspase-1 or caspase-4/5/11-dependent programmed cell death associated with inflammation, which is initiated by inflammasomes or cytosolic LPS in innate immunity. Sepsis is a ...life-threatening organ dysfunction caused by an imbalance in the body’s response to infection. It is a complex interaction between the pathogen and the host’s immune system. Neutrophils play the role of a double-edged sword in sepsis, and a number of studies have previously shown that regulation of neutrophils is the most crucial part of sepsis treatment. Pyroptosis is one of the important forms for neutrophils to function, which is increasingly understood as a host active immune response. There is ample evidence that neutrophil pyroptosis may play an important role in sepsis. In recent years, a breakthrough in pyroptosis research has revealed the main mechanism of pyroptosis. However, the potential value of neutrophil pyroptosis in the treatment of sepsis did not draw enough attention. A literature review was performed on the main mechanism of pyroptosis in sepsis and the potential value of neutrophils pyroptosis in sepsis, which may be suitable targets for sepsis treatment in future.
Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with a plethora of pathogenic products and cellular products associated with stress and damage. By ...far, the best studied and most characterized inflammasome is NLRP3 inflammasome, which consists of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and procaspase-1. Activation of NLRP3 inflammasome is mediated by highly diverse stimuli. Upon activation, NLRP3 protein recruits the adapter ASC protein, which recruits the procaspase-1 resulting in its cleavage and activation, inducing the maturation, and secretion of inflammatory cytokines and pyroptosis. However, aberrant activation of the NLRP3 inflammasome is implicated in various diseases including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, and neurodegenerative diseases; raising a tremendous clinical interest in exploring the potential inhibitors of NLRP3 inflammasome. Recent investigations have disclosed various inhibitors of the NLRP3 inflammasome pathway which were validated through
studies and
experiments in animal models of NLRP3-associated disorders. Some of these inhibitors directly target the NLRP3 protein whereas some are aimed at other components and products of the inflammasome. Direct targeting of NLRP3 protein can be a better choice because it can prevent off target immunosuppressive effects, thus restrain tissue destruction. This paper will review the various pharmacological inhibitors of the NLRP3 inflammasome and will also discuss their mechanism of action.
Sarcopenia is one of the most common skeletal muscle disorders and is characterized by infirmity and disability. While extensive research has focused on elucidating the mechanisms underlying the ...progression of sarcopenia, further comprehensive insights into its pathogenesis are necessary to identify new preventive and therapeutic approaches. The involvement of inflammasomes in sarcopenia is widely recognized, with particular emphasis on the NLRP3 (NLR family pyrin domain containing 3) inflammasome. In this review, we aim to elucidate the underlying mechanisms of the NLRP3 inflammasome and its relevance in sarcopenia of various etiologies. Furthermore, we highlight interventions targeting the NLRP3 inflammasome in the context of sarcopenia and discuss the current limitations of our knowledge in this area.
•Sarcopenia is a skeletal muscle disorder characterized by infirmity and disability.•The involvement of NLRP3 inflammasome in sarcopenia is deeply discussed.•An overview of the current and future therapeutic approaches targeting the NLRP3 inflammasome in sarcopenia.•The NLRP3 inflammasome can be a target for sarcopenia treatment.
Pyroptosis is a type of programmed cell death mediated by a multiprotein complex called the inflammasome through the pro‐inflammatory activity of gasdermin D. This study aimed to recognize the final ...biological product that leads to pore formation in the cell membrane, lysis, pro‐inflammatory cytokines release, and the establishment of an immune response. An exhaustive search engine investigation of an elevated immune response can induce a sustained inflammation that directly links this mechanism to non‐alcoholic fatty liver disease and its progression to non‐alcoholic steatohepatitis. Clinical studies and systematic reviews suggest that gasdermin D is a critical molecule between the immune response and the disease manifestation, which could be considered a therapeutic target for highly prevalent diseases characterized by presenting perpetuated inflammatory processes. Both basic and clinical research show evidence on the expression and regulation of the inflammasome–gasdermin D–pyroptosis trinomial for the progression of non‐alcoholic fatty liver disease to non‐alcoholic steatohepatitis.
Pyroptosis is a form of cell death mediated by gasdermin D (GSDMD); it is characterised by NLRP3 inflammasome activation, caspase activation, cell membrane pore formation, and the release of ...interleukin-1β and interleukin-18. NLRP3 inflammasome activation plays a central role in pyroptosis. Recent research has suggested that NLRP3 inflammasome activation may be involved in the occurrence and development of diabetes mellitus and its associated complications. This finding provided the impetus for us to clarify the significance of pyroptosis in diabetes. In this review, we summarise the current understanding of the molecular mechanisms involved in pyroptosis, as well as recent advances in the role of NLRP3 inflammasome activation and pyroptosis in the development of diabetes and diabetic complications.
The activation mechanisms of NLRP3 inflammasome. Display omitted
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