The Experts below are selected from a list of 40458 Experts worldwide ranked by ideXlab platform
Thirumala-devi Kanneganti - One of the best experts on this subject based on the ideXlab platform.
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Diverging Inflammasome signals in tumorigenesis and potential targeting
Nature Reviews Cancer, 2019Co-Authors: Rajendra Karki, Thirumala-devi KannegantiAbstract:Inflammasome signalling in myeloid cells protects against microbial infections. Aberrant Inflammasome signalling promotes chronic inflammation, which contributes to tumorigenesis. This Review presents an overview of the diverging roles of Inflammasomes in cancer and discusses its targeting potential in anticancer therapy. 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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Inflammasomes and Cancer
Cancer immunology research, 2017Co-Authors: Rajendra Karki, Si Ming Man, Thirumala-devi KannegantiAbstract:Inflammation affects all stages of tumorigenesis. A key signaling pathway leading to acute and chronic inflammation is through activation of the caspase-1 Inflammasome. Inflammasome complexes are assembled on activation of certain nucleotide-binding domain, leucine-rich repeat-containing proteins (NLR), AIM2-like receptors, or pyrin. Of these, NLRP1, NLRP3, NLRC4, NLRP6, and AIM2 influence the pathogenesis of cancer by modulating innate and adaptive immune responses, cell death, proliferation, and/or the gut microbiota. Activation of the Inflammasome and IL18 signaling pathways is largely protective in colitis-associated colorectal cancer, whereas excessive inflammation driven by the Inflammasome or the IL1 signaling pathways promotes breast cancer, fibrosarcoma, gastric carcinoma, and lung metastasis in a context-dependent manner. The clinical relevance of Inflammasomes in multiple forms of cancer highlights their therapeutic promise as molecular targets. In this review, we explore the crossroads between Inflammasomes and the development of various tumors and discuss possible therapeutic values in targeting the Inflammasome for the prevention and treatment of cancer. Cancer Immunol Res; 5(2); 94-99. ©2017 AACR.
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Immune responses against protozoan parasites: a focus on the emerging role of Nod-like receptors
Cellular and Molecular Life Sciences, 2016Co-Authors: Prajwal Gurung, Thirumala-devi KannegantiAbstract:Nod-like receptors (NLRs) have gained attention in recent years because of the ability of some family members to assemble into a multimeric protein complex known as the Inflammasome. The role of NLRs and the Inflammasome in regulating innate immunity against bacterial pathogens has been well studied. However, recent studies show that NLRs and Inflammasomes also play a role during infections caused by protozoan parasites, which pose a significant global health burden. Herein, we review the diseases caused by the most common protozoan parasites in the world and discuss the roles of NLRs and Inflammasomes in host immunity against these parasites.
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Regulation of Inflammasome activation
Immunological reviews, 2015Co-Authors: Si Ming Man, Thirumala-devi KannegantiAbstract: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, autoinflammatory, 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-like receptor (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 to the development of autoinflammatory 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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Inflammasome control of viral infection.
Current opinion in virology, 2015Co-Authors: Christopher Lupfer, Ankit Malik, Thirumala-devi KannegantiAbstract:The Inflammasome is a caspase-1 containing complex that activates the proinflammatory cytokines IL-1β and IL-18 and results in the proinflammatory cell death known as pyroptosis. Numerous recent publications have highlighted the importance of Inflammasome activation in the control of virus infection. Inflammasome activation during viral infection is dependent on a variety of upstream receptors including the NOD-like receptor, RIG-I-like receptor and AIM2-like receptor families. Various receptors also function in Inflammasome activation in different cellular compartments, including the cytoplasm and the nucleus. The effectiveness of Inflammasomes at suppressing virus replication is highlighted by the prevalence and diversity of virus encoded Inflammasome inhibitors. Also, the host has a myriad of regulatory mechanisms in place to prevent unwanted Inflammasome activation and overt inflammation. Finally, recent reports begin to suggest that Inflammasome activation and Inflammasome modulation may have important clinical applications. Herein, we highlight recent advances and discuss potential future directions toward understanding the role of Inflammasomes during virus infection.
Russell E Vance - One of the best experts on this subject based on the ideXlab platform.
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naip nlrc4 Inflammasome activation in mrp8 cells is sufficient to cause systemic inflammatory disease
Nature Communications, 2017Co-Authors: Randilea D Nichols, Jakob Von Moltke, Russell E VanceAbstract:Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can also drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood. Inflammasomes are broadly expressed in haematopoietic and non-haematopoietic cells and can trigger numerous downstream responses including production of IL-1β, IL-18, eicosanoids and pyroptotic cell death. Here we show a mouse model with endogenous NLRC4 Inflammasome activation in Lysozyme2 + cells (monocytes, macrophages and neutrophils) in vivo exhibits a severe systemic inflammatory disease, reminiscent of human patients that carry mutant auto-active NLRC4 alleles. Interestingly, specific NLRC4 activation in Mrp8 + cells (primarily neutrophil lineage) is sufficient to cause severe inflammatory disease. Disease is ameliorated on an Asc −/− background, and can be suppressed by injections of anti-IL-1 receptor antibody. Our results provide insight into the mechanisms by which NLRC4 Inflammasome activation mediates auto-inflammatory disease in vivo. Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent Inflammasome activation in neutrophils contributes to systemic inflammation.
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NAIP/NLRC4 Inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease.
Nature Communications, 2017Co-Authors: Randilea D Nichols, Jakob Von Moltke, Russell E VanceAbstract:Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can also drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood. Inflammasomes are broadly expressed in haematopoietic and non-haematopoietic cells and can trigger numerous downstream responses including production of IL-1β, IL-18, eicosanoids and pyroptotic cell death. Here we show a mouse model with endogenous NLRC4 Inflammasome activation in Lysozyme2 + cells (monocytes, macrophages and neutrophils) in vivo exhibits a severe systemic inflammatory disease, reminiscent of human patients that carry mutant auto-active NLRC4 alleles. Interestingly, specific NLRC4 activation in Mrp8 + cells (primarily neutrophil lineage) is sufficient to cause severe inflammatory disease. Disease is ameliorated on an Asc −/− background, and can be suppressed by injections of anti-IL-1 receptor antibody. Our results provide insight into the mechanisms by which NLRC4 Inflammasome activation mediates auto-inflammatory disease in vivo. Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent Inflammasome activation in neutrophils contributes to systemic inflammation.
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the nlrp1 Inflammasomes
Immunological Reviews, 2015Co-Authors: Joseph Chavarriasmith, Russell E VanceAbstract:Summary Inflammasomes are cytosolic protein complexes that serve as platforms for the recruitment and activation of the pro-inflammatory CASPASE-1 protease. CASPASE-1 activation leads to processing and maturation of the cytokines interleukin-1β and interleukin-18 and a lytic form of cell death termed pyroptosis. Inflammasome assembly is initiated by cytosolic sensors in response to microbial infections. Many of these sensors, including NLRP1 (NLR family, pyrin domain containing 1), are described to form an Inflammasome, but until recently, the mechanism of Inflammasome activation and its physiological functions in host defense have remained unclear. In the last few years, important advances in our understanding of NLRP1 biology have been achieved. In this review, we discuss the activation of NLRP1 by various stimuli, including Bacillus anthracis lethal toxin, Toxoplasma gondii, muramyl dipeptide, and host intracellular ATP depletion. The role NLRP1 plays in pathogen recognition and resistance during infection is also discussed, as is the regulation of NLRP1 by host and viral proteins. We conclude by discussing the unexpected differences in the mechanism of NLRP1 Inflammasome activation, as compared to the activation of other Inflammasomes, such as the NAIP (NLR family, apoptosis inhibitory protein)/NLRC4 Inflammasomes.
Mohamed Lamkanfi - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic modulation of Inflammasome pathways.
Immunological reviews, 2020Co-Authors: Dhruv Chauhan, Lieselotte Vande Walle, Mohamed LamkanfiAbstract:Inflammasomes are macromolecular complexes formed in response to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) that drive maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and cleave gasdermin D (GSDMD) for induction of pyroptosis. Inflammasomes are highly important in protecting the host from various microbial pathogens and sterile insults. Inflammasome pathways are strictly regulated at both transcriptional and post-translational checkpoints. When these checkpoints are not properly imposed, undue Inflammasome activation may promote inflammatory, metabolic and oncogenic processes that give rise to autoinflammatory, autoimmune, metabolic and malignant diseases. In addition to clinically approved IL-1-targeted biologics, upstream targeting of Inflammasome pathways recently gained interest as a novel pharmacological strategy for selectively modulating Inflammasome activation in pathological conditions.
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Inflammasomes in neuroinflammatory and neurodegenerative diseases.
EMBO molecular medicine, 2019Co-Authors: Sofie Voet, Mohamed Lamkanfi, Sahana Srinivasan, Geert Van LooAbstract:Abstract Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate Inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)‐1β and IL‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for Inflammasome activation. However, additional CNS‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate Inflammasomes. In this review, we will discuss current understanding of the role of Inflammasomes in common degenerative diseases of the brain and highlight Inflammasome‐targeted strategies that may potentially treat these diseases.
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Protective and detrimental roles of Inflammasomes in disease
Seminars in Immunopathology, 2015Co-Authors: Pedro H. V. Saavedra, Dieter Demon, Hanne Gorp, Mohamed LamkanfiAbstract:Over recent years, Inflammasomes have emerged as key regulators of immune and inflammatory responses. They induce programmed cell death and direct the release of danger signals and the inflammatory cytokines interleukin (IL)-1β and IL-18. The concerted actions of Inflammasomes are of utmost importance for responding adequately to harmful environmental agents and infections. However, deregulated Inflammasome signaling is increasingly linked to a diversity of human pathologies, including rheumatoid arthritis, inflammatory bowel disease, and rare, hereditary periodic fever syndromes. In this review, we discuss recent insight in the protective and detrimental roles of Inflammasomes in selected infectious, autoinflammatory and autoimmune diseases, and cover clinically approved therapies that interfere with Inflammasome signaling. These findings highlight the importance of fine-balancing the Ying and Yang activities of Inflammasomes for sustained homeostasis and suggest that further understanding of Inflammasome mechanisms may offer new cures for human diseases.
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Mechanisms and Functions of Inflammasomes
Cell, 2014Co-Authors: Mohamed Lamkanfi, Vishva M. DixitAbstract:Recent studies have offered a glimpse into the sophisticated mechanisms by which Inflammasomes respond to danger and promote secretion of interleukin (IL)-1β and IL-18. Activation of caspases 1 and 11 in canonical and noncanonical Inflammasomes, respectively, also protects against infection by triggering pyroptosis, a proinflammatory and lytic mode of cell death. The therapeutic potential of inhibiting these proinflammatory caspases in infectious and autoimmune diseases is raised by the successful deployment of anti-IL-1 therapies to control autoinflammatory diseases associated with aberrant Inflammasome signaling. This Review summarizes recent insights into Inflammasome biology and discusses the questions that remain in the field.
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Deregulated Inflammasome signaling in disease
Immunological reviews, 2011Co-Authors: Mohamed Lamkanfi, Lieselotte Vande Walle, Thirumala-devi KannegantiAbstract:Inflammasomes are multi-protein complexes that sense microbial molecules and endogenous danger signals in intracellular compartments. Inflammasome assembly results in caspase-1 activation, which in turn drives maturation and secretion of the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18, and induces pyroptosis to eliminate the infectious agent. The importance of Inflammasomes in regulating immune responses was recognized with the discovery of polymorphisms in genes encoding Inflammasome components and their linkage to aberrant production of IL-1β and IL-18 in autoimmune and hereditary periodic fevers syndromes. We review the current knowledge on the role of Inflammasomes in regulating innate and adaptive immune responses with an emphasis on the role of these immune complexes in autoinflammatory disorders and autoimmune diseases such as colitis, type I diabetes, multiple sclerosis and vitiligo.
Fabio Martinon - One of the best experts on this subject based on the ideXlab platform.
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Detection of viruses by Inflammasomes.
Current opinion in virology, 2020Co-Authors: Lotte Spel, Fabio MartinonAbstract:The innate immune system has evolved mechanisms to keep the viral infection under control and repair damaged tissues. Several pathways can identify the presence of pathogenic components, such as viral nucleic acids and viral proteins. Also, the innate immune system can detect cellular and tissue perturbations caused by infections. Inflammasomes are cellular pieces of machinery that can detect a pathogen's presence and its possible impact on cellular integrity. Thereby several Inflammasomes, including the NLRP3 Inflammasome and the AIM2 Inflammasome, contribute to antiviral innate immunity. Inflammation driven by Inflammasomes promotes immune defenses and initiate repair mechanisms. However, its overactivation may trigger acute inflammatory responses that may harm the host. This pathologic activation could contribute to the hyperinflammatory response observed in patients infected with viruses, including influenza, SARS, and possibly SARS-CoV2.
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signaling by ros drives Inflammasome activation
European Journal of Immunology, 2010Co-Authors: Fabio MartinonAbstract:Inflammasomes are innate immune signaling pathways that sense pathogens and injury to direct the proteolytic maturation of inflammatory cytokines such as IL-1beta and IL-18. Among Inflammasomes, the NLRP3/NALP3 Inflammasome is the most studied. However, little is known on the molecular mechanisms that mediate its assembly and activation. Recent findings suggest that ROS are produced by NLRP3/NALP3 activators and are essential secondary messengers signaling NLRP3/NALP3 Inflammasome activation.
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Activation of the NALP3 Inflammasome is triggered by low intracellular potassium concentration
Cell Death & Differentiation, 2007Co-Authors: Virgine Pétrilli, Fabio Martinon, Sophie Papin, Catherine Dostert, A Mayor, Jürg TschoppAbstract:Inflammasomes are Nod-like receptor(NLR)- and caspase-1-containing cytoplasmic multiprotein complexes, which upon their assembly, process and activate the proinflammatory cytokines interleukin (IL)-1 β and IL-18. The Inflammasomes harboring the NLR members NALP1, NALP3 and IPAF have been best characterized. While the IPAF Inflammasome is activated by bacterial flagellin, activation of the NALP3 Inflammasome is triggered not only by several microbial components, but also by a plethora of danger-associated host molecules such as uric acid. How NALP3 senses these chemically unrelated activators is not known. Here, we provide evidence that activation of NALP3, but not of the IPAF Inflammasome, is blocked by inhibiting K^+ efflux from cells. Low intracellular K^+ is also a requirement for NALP1 Inflammasome activation by lethal toxin of Bacillus anthracis . In vitro , NALP Inflammasome assembly and caspase-1 recruitment occurs spontaneously at K^+ concentrations below 90 m M , but is prevented at higher concentrations. Thus, low intracellular K^+ may be the least common trigger of NALP-Inflammasome activation.
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Activation of the NALP3 Inflammasome is triggered by low intracellular potassium concentration.
Cell death and differentiation, 2007Co-Authors: Virgine Pétrilli, Fabio Martinon, Sophie Papin, Catherine Dostert, A Mayor, Juerg TschoppAbstract:Inflammasomes are Nod-like receptor(NLR)- and caspase-1-containing cytoplasmic multiprotein complexes, which upon their assembly, process and activate the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The Inflammasomes harboring the NLR members NALP1, NALP3 and IPAF have been best characterized. While the IPAF Inflammasome is activated by bacterial flagellin, activation of the NALP3 Inflammasome is triggered not only by several microbial components, but also by a plethora of danger-associated host molecules such as uric acid. How NALP3 senses these chemically unrelated activators is not known. Here, we provide evidence that activation of NALP3, but not of the IPAF Inflammasome, is blocked by inhibiting K(+) efflux from cells. Low intracellular K(+) is also a requirement for NALP1 Inflammasome activation by lethal toxin of Bacillus anthracis. In vitro, NALP Inflammasome assembly and caspase-1 recruitment occurs spontaneously at K(+) concentrations below 90 mM, but is prevented at higher concentrations. Thus, low intracellular K(+) may be the least common trigger of NALP-Inflammasome activation.
Jakob Von Moltke - One of the best experts on this subject based on the ideXlab platform.
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naip nlrc4 Inflammasome activation in mrp8 cells is sufficient to cause systemic inflammatory disease
Nature Communications, 2017Co-Authors: Randilea D Nichols, Jakob Von Moltke, Russell E VanceAbstract:Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can also drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood. Inflammasomes are broadly expressed in haematopoietic and non-haematopoietic cells and can trigger numerous downstream responses including production of IL-1β, IL-18, eicosanoids and pyroptotic cell death. Here we show a mouse model with endogenous NLRC4 Inflammasome activation in Lysozyme2 + cells (monocytes, macrophages and neutrophils) in vivo exhibits a severe systemic inflammatory disease, reminiscent of human patients that carry mutant auto-active NLRC4 alleles. Interestingly, specific NLRC4 activation in Mrp8 + cells (primarily neutrophil lineage) is sufficient to cause severe inflammatory disease. Disease is ameliorated on an Asc −/− background, and can be suppressed by injections of anti-IL-1 receptor antibody. Our results provide insight into the mechanisms by which NLRC4 Inflammasome activation mediates auto-inflammatory disease in vivo. Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent Inflammasome activation in neutrophils contributes to systemic inflammation.
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NAIP/NLRC4 Inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease.
Nature Communications, 2017Co-Authors: Randilea D Nichols, Jakob Von Moltke, Russell E VanceAbstract:Inflammasomes are cytosolic multiprotein complexes that initiate protective immunity in response to infection, and can also drive auto-inflammatory diseases, but the cell types and signalling pathways that cause these diseases remain poorly understood. Inflammasomes are broadly expressed in haematopoietic and non-haematopoietic cells and can trigger numerous downstream responses including production of IL-1β, IL-18, eicosanoids and pyroptotic cell death. Here we show a mouse model with endogenous NLRC4 Inflammasome activation in Lysozyme2 + cells (monocytes, macrophages and neutrophils) in vivo exhibits a severe systemic inflammatory disease, reminiscent of human patients that carry mutant auto-active NLRC4 alleles. Interestingly, specific NLRC4 activation in Mrp8 + cells (primarily neutrophil lineage) is sufficient to cause severe inflammatory disease. Disease is ameliorated on an Asc −/− background, and can be suppressed by injections of anti-IL-1 receptor antibody. Our results provide insight into the mechanisms by which NLRC4 Inflammasome activation mediates auto-inflammatory disease in vivo. Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent Inflammasome activation in neutrophils contributes to systemic inflammation.
