ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z‐RNA produced during influenza virus ...infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co‐regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1‐NLRP3 inflammasome. When Z‐RNA is sensed, ZBP1 recruits RIPK3 and caspase‐8 to activate the ZBP1‐NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1‐NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase‐6. Additionally, influenza viral proteins, such as M2, NS1, and PB1‐F2, have also been shown to regulate the ZBP1‐NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1‐NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1‐NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation ...and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1β or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome-mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections ...are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Inflammasomes are multimeric protein complexes that typically comprise a sensor, an adaptor and the zymogen procaspase-1. An inflammasome assembles in response to a diverse range of ...pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage, which further induces maturation of interleukins 1β and 18 (IL-1β and IL-18) through proteolytic cleavage of pro-IL-1β and pro-IL-18. Activated caspase-1 also cleaves gasdermin D, which leads to a particular form of cell death called pyroptosis. Mutations in genes that encode inflammasome components are associated with many inflammatory disorders, and studies in the past decade have highlighted the importance of appropriate activation of the inflammasome in homeostasis and disease pathogenesis. Therefore, much attention is being paid to uncover the modulators and regulators of inflammasome assembly and pyroptosis. This Cell Science at a Glance article and accompanying poster outlines the concepts in the activation of inflammasome sensors and assembly of the inflammasome platform. We also discuss recent insights into the mechanisms of regulation of inflammasome activity and the induction of cell death by pyroptosis.
Regulation of inflammasome activation Man, Si Ming; Kanneganti, Thirumala-Devi
Immunological reviews,
20/May , Volume:
265, Issue:
1
Journal Article
Peer reviewed
Open access
Summary
Inflammasome biology is one of the most exciting and rapidly growing areas in immunology. Over the past 10 years, inflammasomes have been recognized for their roles in the host defense ...against invading pathogens and in the development of cancer, auto‐inflammatory, metabolic, and neurodegenerative diseases. Assembly of an inflammasome complex requires cytosolic sensing of pathogen‐associated molecular patterns or danger‐associated molecular patterns by a nucleotide‐binding domain and leucine‐rich repeat receptor (NLR) or absent in melanoma 2 (AIM2)‐like receptors (ALR). NLRs and ALRs engage caspase‐1, in most cases requiring the adapter protein apoptosis‐associated speck‐like protein containing a CARD (ASC), to catalyze proteolytic cleavage of pro‐interleukin‐1β (pro‐IL‐1β) and pro‐IL‐18 and drive pyroptosis. Recent studies indicate that caspase‐8, caspase‐11, IL‐1R–associated kinases (IRAK), and receptor‐interacting protein (RIP) kinases contribute to inflammasome functions. In addition, post‐translational modifications, including ubiquitination, deubiquitination, phosphorylation, and degradation control almost every aspect of inflammasome activities. Genetic studies indicate that mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked with the development of auto‐inflammatory diseases, enterocolitis, and cancer. Overall, these findings transform our understanding of the basic biology and clinical relevance of inflammasomes. In this review, we provide an overview of the latest development of inflammasome research and discuss how inflammasome activities govern health and disease.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Cell death is a fundamental biological phenomenon that is essential for the survival and development of an organism. Emerging evidence also indicates that cell death contributes to immune ...defense against infectious diseases. Pyroptosis is a form of inflammatory programmed cell death pathway activated by human and mouse caspase‐1, human caspase‐4 and caspase‐5, or mouse caspase‐11. These inflammatory caspases are used by the host to control bacterial, viral, fungal, or protozoan pathogens. Pyroptosis requires cleavage and activation of the pore‐forming effector protein gasdermin D by inflammatory caspases. Physical rupture of the cell causes release of the pro‐inflammatory cytokines IL‐1β and IL‐18, alarmins and endogenous danger‐associated molecular patterns, signifying the inflammatory potential of pyroptosis. Here, we describe the central role of inflammatory caspases and pyroptosis in mediating immunity to infection and clearance of pathogens.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Inflammasomes are molecular platforms that assemble upon sensing various intracellular stimuli. Inflammasome assembly leads to activation of caspase 1, thereby promoting the secretion of bioactive ...interleukin-1β (IL-1β) and IL-18 and inducing an inflammatory cell death called pyroptosis. Effectors of the inflammasome efficiently drive an immune response, primarily providing protection against microbial infections and mediating control over sterile insults. However, aberrant inflammasome signalling is associated with pathogenesis of inflammatory and metabolic diseases, neurodegeneration and malignancies. Chronic inflammation perpetuated by inflammasome activation plays a central role in all stages of tumorigenesis, including immunosuppression, proliferation, angiogenesis and metastasis. Conversely, inflammasome signalling also contributes to tumour suppression by maintaining intestinal barrier integrity, which portrays the diverse roles of inflammasomes in tumorigenesis. Studies have underscored the importance of environmental factors, such as diet and gut microbiota, in inflammasome signalling, which in turn influences tumorigenesis. In this Review, we deliver an overview of the interplay between inflammasomes and tumorigenesis and discuss their potential as therapeutic targets.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cytokine storm syndrome (CSS) has generally been described as a collection of clinical manifestations resulting from an overactivated immune system. Cytokine storms (CSs) are associated with various ...pathologies, as observed in infectious diseases, certain acquired or inherited immunodeficiencies and autoinflammatory diseases, or following therapeutic interventions. Despite the role of CS in tissue damage and multiorgan failure, a systematic understanding of its underlying molecular mechanisms is lacking. Recent studies demonstrate a positive feedback loop between cytokine release and cell death pathways; certain cytokines, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), can activate inflammatory cell death, leading to further cytokine secretion. Here, we discuss recent progress in innate immunity and inflammatory cell death, providing insights into the cellular and molecular mechanisms of CSs and therapeutics that might quell ensuing life-threatening effects.
A cytokine storm (CS) is a clinically relevant condition that has been associated with several life-threatening diseases.Although CS syndrome-inducing agents can fundamentally differ, the interactions of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) with pattern recognition receptors evoke similar cytokine profiles in mammals.Cytokines are intricately linked to cell death mechanisms in mammals and are involved in a positive feedback loop, whereby cytokine signaling or PAMP/DAMP sensing causes inflammatory cell death that facilitates further pathogenic cytokine release, culminating in a CS to drive severe, life-threatening damage to host tissues and organs.Neutralization of tumor necrosis factor (TNF) and interferon (IFN)-γ can prevent cell death and inhibit the occurrence of a CS in mouse models of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, hemophagocytic lymphohistiocytosis, and sepsis.A combination of US FDA-approved drugs might be more beneficial than single-treatment approaches for the clinical management of CSs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Over the past decade, numerous advances have been made in the role and regulation of inflammasomes during pathogenic and sterile insults. An inflammasome complex comprises a sensor, an adaptor, and a ...zymogen procaspase-1. The functional output of inflammasome activation includes secretion of cytokines, IL-1β and IL-18, and induction of an inflammatory form of cell death called pyroptosis. Recent studies have highlighted the intersection of this inflammatory response with fundamental cellular processes. Novel modulators and functions of inflammasome activation conventionally associated with the maintenance of homeostatic biological functions have been uncovered. In this review, we discuss the biological processes involved in the activation and regulation of the inflammasome.
The innate immune system acts as the first line of defense against pathogens, including coronaviruses (CoVs). Severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome ...(MERS)-CoV are epidemic zoonotic CoVs that emerged at the beginning of the 21st century. The recently emerged virus SARS-CoV-2 is a novel strain of CoV that has caused the coronavirus 2019 (COVID-19) pandemic. Scientific advancements made by studying the SARS-CoV and MERS-CoV outbreaks have provided a foundation for understanding pathogenesis and innate immunity against SARS-CoV-2. In this review, we focus on our present understanding of innate immune responses, inflammasome activation, inflammatory cell death pathways, and cytokine secretion during SARS-CoV, MERS-CoV, and SARS-CoV-2 infection. We also discuss how the pathogenesis of these viruses influences these biological processes.
Toll-like receptor (TLR)- and retinoic acid-inducible gene I-like receptor (RLR)-mediated type I interferon (IFN) production is essential for providing protection against coronavirus (CoV) infection; the timing of the IFN response relative to CoV replication determines infection outcomes.Optimal NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation is beneficial for the host but aberrant activation may lead to detrimental CoV infection outcomes.Specific CoV infections can activate inflammatory cell death (PANoptosis), thereby inducing cytokine release.CoV disease tolerance occurs in age-, species-, and sex-dependent manners.More studies are needed to define the innateimmune response, specifically during severe acute respiratory syndrome (SARS)-CoV-2 (SARS-CoV-2) infection, and to informthe development of candidate therapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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