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
The innate immune response is critical for recognizing and controlling infections through the release of cytokines and chemokines. However, severe pathology during some infections, including ...SARS-CoV-2, is driven by hyperactive cytokine release, or a cytokine storm. The innate sensors that activate production of proinflammatory cytokines and chemokines during COVID-19 remain poorly characterized. In the present study, we show that both TLR2 and MYD88 expression were associated with COVID-19 disease severity. Mechanistically, TLR2 and Myd88 were required for β-coronavirus-induced inflammatory responses, and TLR2-dependent signaling induced the production of proinflammatory cytokines during coronavirus infection independent of viral entry. TLR2 sensed the SARS-CoV-2 envelope protein as its ligand. In addition, blocking TLR2 signaling in vivo provided protection against the pathogenesis of SARS-CoV-2 infection. Overall, our study provides a critical understanding of the molecular mechanism of β-coronavirus sensing and inflammatory cytokine production, which opens new avenues for therapeutic strategies to counteract the ongoing COVID-19 pandemic.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The innate immune system serves as the first line of defense against invading pathogens; however, dysregulated innate immune responses can induce aberrant inflammation that is detrimental to the ...host. Therefore, careful innate immune regulation is critical during infections. The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in global morbidity and mortality as well as socio-economic stresses. Innate immune sensing of SARS-CoV-2 by multiple host cell pattern recognition receptors leads to the production of various pro-inflammatory cytokines and the induction of inflammatory cell death. These processes can contribute to cytokine storm, tissue damage, and acute respiratory distress syndrome. Here, we discuss the sensing of SARS-CoV-2 to induce innate immune activation and the contribution of this innate immune signaling in the development and severity of COVID-19. In addition, we provide a conceptual framework for innate immunity driving cytokine storm and organ damage in patients with severe COVID-19. A better understanding of the molecular mechanisms regulated by innate immunity is needed for the development of targeted modalities that can improve patient outcomes by mitigating severe disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, 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
AIM2 is a cytosolic innate immune receptor which recognizes double‐stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly ...of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin‐1β (IL‐1β) and IL‐18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.
AIM2 recognises double‐stranded DNA released during pathogenic assault or host cellular damage, resulting in activation of the AIM2 inflammasome. The AIM2 inflammasome promotes sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, diabetes and atherosclerosis. However, it is largely protective during infectious diseases and colon cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Inflammasomes and Cancer Karki, Rajendra; Man, Si Ming; Kanneganti, Thirumala-Devi
Cancer immunology research,
02/2017, Volume:
5, Issue:
2
Journal Article
Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host ...origin. Upon binding to DNA, AIM2 assembles a multiprotein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the proinflammatory cytokines pro‐IL‐1β and pro‐IL‐18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus, and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self‐DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and inflammatory diseases. Inflammasome‐independent functions of AIM2 have also been described, including the regulation of the intestinal stem cell proliferation and the gut microbiota ecology in the control of colorectal cancer. In this review we provide an overview of the latest research on AIM2 inflammasome and its role in infection, cancer, and autoimmunity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, ...whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases.
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•Combining IFNs with NEIs induces ZBP1-mediated inflammatory cell death, PANoptosis•ADAR1 negatively regulates the ZBP1-mediated PANoptosis•Blocking ADAR1 activity unleashes ZBP1-mediated PANoptosis to inhibit tumorigenesis•In mice, IFN-γ + KPT-330 dramatically regresses tumors in a ZBP1-dependent manner
Karki et al. identify a critical role for ADAR1 in regulating ZBP1-mediated inflammatory cell death, PANoptosis. Treating with IFNs, which upregulate ADAR1 and ZBP1, and nuclear export inhibitors, which sequester ADAR1 in the nucleus, induces robust cell death that inhibits tumorigenesis in vivo, suggesting a therapeutic strategy.
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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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