•The NLRP3, NLRC4, and pyrin inflammasomes are regulated by post-translational modifications.•The Dhx9-NLRP9b inflammasome recognizing viral dsRNA was recently identified in intestinal ...cells.•Gasdermin family proteins are cleaved by caspases to form pores in cells and execute cell death.
The inflammasome is a complex of proteins that through the activity of caspase-1 and the downstream substrates gasdermin D, IL-1β, and IL-18 execute an inflammatory form of cell death termed pyroptosis. Activation of this complex often involves the adaptor protein ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. Here we discuss new regulatory mechanisms that have been identified for the canonical inflammasomes, the most recently identified NLRP9b inflammasome, and the new gasdermin family of proteins that mediate pyroptosis and other forms of regulated cell death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Targeting apoptosis to treat diseases has seen tremendous success over the past decades. More recently, alternative forms of regulated cell death, including pyroptosis and necroptosis, have been ...described. Understanding the molecular cascades regulating both pyroptosis and necroptosis will yield even more targets to treat diseases. These lytic forms of cell death are distinct from apoptosis due to their characteristic lysis and release of cellular components that promote disease or direct a beneficial immune response. In this review, we focus on how pyroptosis and necroptosis, which release potent immune cytokines such as IL-1 and IL-18, contribute to various diseases. We also consider the important role that the executioners of these cell death pathways, GSDMD and MLKL, play in the progression of inflammatory diseases. Crosstalk between the different cell death pathways likely plays a major role physiologically. New therapeutic strategies targeting these specific molecules hold enormous potential for managing inflammatory diseases.
DNA Sensing in the Innate Immune Response Briard, Benoit; Place, David E; Kanneganti, Thirumala-Devi
Physiology (Bethesda, Md.),
03/2020, Volume:
35, Issue:
2
Journal Article
Peer reviewed
Open access
The innate immune system recognizes conserved pathogen-associated molecular patterns and produces inflammatory cytokines that direct downstream immune responses. The inappropriate localization of DNA ...within the cell cytosol or endosomal compartments indicates that a cell may either be infected by a DNA virus or bacterium, or has problems with its own nuclear integrity. This DNA is sensed by certain receptors that mediate cytokine production and, in some cases, initiate an inflammatory and lytic form of cell death called pyroptosis. Dysregulation of these DNA-sensing pathways is thought to contribute to autoimmune diseases and the development of cancer. In this review, we will discuss the DNA sensors Toll-like receptor 9 (TLR9), cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), absent in melanoma 2 (AIM2), and interferon gamma-inducible 16 (IFI16), their ligands, and their physiological significance. We will also examine the less-well-understood DEAH- and DEAD-box helicases DHX9, DHX36, DDX41, and RNA polymerase III, each of which may play an important role in DNA-mediated innate immunity.
Inflammasomes are multi-component signaling complexes critical to the initiation of pyroptotic cell death in response to invading pathogens and cellular damage. A number of innate immune receptors ...have been reported to serve as inflammasome sensors. Activation of these sensors leads to the proteolytic activation of caspase-1, a proinflammatory caspase responsible for the cleavage of proinflammatory cytokines interleukin-1β and interleukin-18 and the effector of pyroptotic cell death, gasdermin D. Though crucial to the innate immune response to infection, dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. Therefore, clinical interest in the modulation of inflammasome activation is swiftly growing. As such, it is imperative to develop a mechanistic understanding of the regulation of these complexes. In this review, we divide the regulation of inflammasome activation into three parts. We discuss the transcriptional regulation of inflammasome components and related proteins, the post-translational mechanisms of inflammasome activation, and advances in the understanding of the structural basis of inflammasome activation.
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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
PANoptosis in microbial infection Place, David E; Lee, SangJoon; Kanneganti, Thirumala-Devi
Current opinion in microbiology,
02/2021, Volume:
59
Journal Article
Peer reviewed
Open access
•Cells exposed to TLR ligands and cytokines during infection activate PANoptosis.•RIPK1-dependent PANoptosome is formed when cell survival signaling is inhibited.•Influenza A virus Z-RNAs bind and ...activate ZBP1, promoting PANoptosome formation.
The immune system has evolved multiple mechanisms to restrict microbial infections and regulate inflammatory responses. Without appropriate regulation, infection-induced inflammatory pathology can be deadly. The innate immune system recognizes the microbial molecules conserved in many pathogens and engages a rapid response by producing inflammatory mediators and activating programmed cell death pathways, including pyroptosis, apoptosis, and necroptosis. Activation of pattern recognition receptors, in combination with inflammatory cytokine-induced signaling through death domain-containing receptors, initiates a highly interconnected cell death process called PANoptosis (pyroptosis, apoptosis, necroptosis). Broadly speaking, PANoptosis is critical for restricting a wide range of pathogens (including bacteria, viruses, fungi, and parasites), which we describe in this review. We propose that re-examining the role of cell death and inflammatory cytokines through the lens of PANoptosis will advance our understanding of host–pathogen evolution and may reveal new treatment strategies for controlling a wide range of infectious diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The cellular stress response has a vital role in regulating homeostasis by modulating cell survival and death. Stress granules are cytoplasmic compartments that enable cells to survive various ...stressors. Defects in the assembly and disassembly of stress granules are linked to neurodegenerative diseases, aberrant antiviral responses and cancer
. Inflammasomes are multi-protein heteromeric complexes that sense molecular patterns that are associated with damage or intracellular pathogens, and assemble into cytosolic compartments known as ASC specks to facilitate the activation of caspase-1. Activation of inflammasomes induces the secretion of interleukin (IL)-1β and IL-18 and drives cell fate towards pyroptosis-a form of programmed inflammatory cell death that has major roles in health and disease
. Although both stress granules and inflammasomes can be triggered by the sensing of cellular stress, they drive contrasting cell-fate decisions. The crosstalk between stress granules and inflammasomes and how this informs cell fate has not been well-studied. Here we show that the induction of stress granules specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The stress granule protein DDX3X interacts with NLRP3 to drive inflammasome activation. Assembly of stress granules leads to the sequestration of DDX3X, and thereby the inhibition of NLRP3 inflammasome activation. Stress granules and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell-fate decisions under stress conditions. Induction of stress granules or loss of DDX3X in the myeloid compartment leads to a decrease in the production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages use the availability of DDX3X to interpret stress signals and choose between pro-survival stress granules and pyroptotic ASC specks. Together, our data demonstrate the role of DDX3X in driving NLRP3 inflammasome and stress granule assembly, and suggest a rheostat-like mechanistic paradigm for regulating live-or-die cell-fate decisions under stress conditions.
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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
•Innate immune signaling components (RIPK1, TAK1 and ZBP1) are critical regulators of inflammation and programmed cell death.•Innate signaling connected with pyroptosis, apoptosis, necroptosis, and ...PANoptosis promotes inflammatory diseases.•Understanding molecular mechanisms of programmed cell death provides new therapeutic targets to treat inflammatory diseases.
The innate immune system, the first line of defense against pathogens and host tissue damage, initiates pro-inflammatory responses which, when dysregulated, promote inflammation to drive a broad range of autoimmune diseases. Immunomodulatory therapies have been developed to successfully treat several autoimmune diseases, but still many others lack effective treatments. Here, we explore recent advances in how the innate immune system contributes to autoinflammation, from the innate immune sensors that initiate immune responses to how this system regulates the activation of programmed cell death pathways including pyroptosis, apoptosis, necroptosis, and PANoptosis, which involves machinery from the pyroptotic, apoptotic, and necroptotic pathways. Recent advances in our understanding of innate immunity raise important considerations for developing new inflammatory disease treatments that target innate immune signaling and programmed cell death pathways.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Programmed cell death plays crucial roles in organismal development and host defense. Recent studies have highlighted mechanistic overlaps and extensive, multifaceted crosstalk between pyroptosis, ...apoptosis, and necroptosis, three programmed cell death pathways traditionally considered autonomous. The growing body of evidence, in conjunction with the identification of molecules controlling the concomitant activation of all three pathways by pathological triggers, has led to the development of the concept of PANoptosis. During PANoptosis, inflammatory cell death occurs through the collective activation of pyroptosis, apoptosis, and necroptosis, which can circumvent pathogen-mediated inhibition of individual death pathways. Many of the molecular details of this emerging pathway are unclear. Here, we describe the activation of PANoptosis by bacterial and viral triggers and report protein interactions that reveal the formation of a PANoptosome complex. Infection of macrophages with influenza A virus, vesicular stomatitis virus,
, or
serovar Typhimurium resulted in robust cell death and the hallmarks of PANoptosis activation. Combined deletion of the PANoptotic components caspase-1 (CASP1), CASP11, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and CASP8 largely protected macrophages from cell death induced by these pathogens, while deletion of individual components provided reduced or no protection. Further, molecules from the pyroptotic, apoptotic, and necroptotic cell death pathways interacted to form a single molecular complex that we have termed the PANoptosome. Overall, our study identifies pathogens capable of activating PANoptosis and the formation of a PANoptosome complex.
Inflammasomes are important sentinels of innate immune defence that are activated in response to diverse stimuli, including pathogen-associated molecular patterns (PAMPs).sup.1. Activation of the ...inflammasome provides host defence against aspergillosis.sup.2,3, which is a major health concern for patients who are immunocompromised. However, the Aspergillus fumigatus PAMPs that are responsible for inflammasome activation are not known. Here we show that the polysaccharide galactosaminogalactan (GAG) of A. fumigatus is a PAMP that activates the NLRP3 inflammasome. The binding of GAG to ribosomal proteins inhibited cellular translation machinery, and thus activated the NLRP3 inflammasome. The galactosamine moiety bound to ribosomal proteins and blocked cellular translation, which triggered activation of the NLRP3 inflammasome. In mice, a GAG-deficient Aspergillus mutant (DELTAgt4c) did not elicit protective activation of the inflammasome, and this strain exhibited enhanced virulence. Moreover, administration of GAG protected mice from colitis induced by dextran sulfate sodium in an inflammasome-dependent manner. Thus, ribosomes connect the sensing of this fungal PAMP to the activation of an innate immune response.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the ...pro-inflammatory cytokines IL-1β and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria. IRGB10 directly targeted cytoplasmic bacteria through a mechanism requiring guanylate-binding proteins. Localization of IRGB10 to the bacterial cell membrane compromised bacterial structural integrity and mediated cytosolic release of ligands for recognition by inflammasome sensors. Overall, our results reveal IRGB10 as part of a conserved signaling hub at the interface between cell-autonomous immunity and innate immune sensing pathways.
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•IRGB10 is required for activation of multiple inflammasomes by bacteria•Recruitment of IRGB10 to the bacteria is dependent on GBPs•IRGB10 targeted bacterial cell membrane and mediated bacterial killing•IRGB10 liberated ligands and provided a conserved signaling hub for inflammasomes
Finding the route to the cytoplasm: an interferon-inducible protein localizes to the cell membrane of bacteria, compromising its structural integrity and mediating release of ligands, otherwise inaccessible, for sensing by inflammasomes.
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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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