Recent Insights into the Molecular Mechanisms Underlying Pyroptosis and Gasdermin Family Functions

Aglietti, Robin A.; Dueber, Erin C.

doi:10.1016/j.it.2017.01.003

Cited by 318 publications

(238 citation statements)

References 83 publications

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“…g) and the secretion of IL‐1 β and IL‐18 (Fig. j) by generating pores within the cell membrane during the caspase‐11 non‐canonical inflammasome response in macrophages …”

Section: Non‐canonical Inflammasome Activation During Inflammatory Rementioning

confidence: 99%

Caspase‐11 non‐canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage‐mediated inflammatory responses

2017

Immunology

189

216

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SummaryInflammatory responses mediated by macrophages are part of the innate immune system, whose role is to protect against invading pathogens. Lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria stimulates an inflammatory response by macrophages. During the inflammatory response, extracellular LPS is recognized by Toll-like receptor 4, one of the pattern recognition receptors that activates inflammatory signalling pathways and leads to the production of inflammatory mediators. The innate immune response is also triggered by intracellular inflammasomes, and inflammasome activation induces pyroptosis and the secretion of pro-inflammatory cytokines such as interleukin-1b (IL-1b) and IL-18 by macrophages. Cysteine-aspartic protease (caspase)-11 and the human orthologues caspase-4/caspase-5 were recently identified as components of the 'non-canonical inflammasome' that senses intracellular LPS derived from Gram-negative bacteria during macrophage-mediated inflammatory responses. Direct recognition of intracellular LPS facilitates the rapid oligomerization of caspase-11/4/5, which results in pyroptosis and the secretion of IL-1b and IL-18. LPS is released into the cytoplasm from Gram-negative bacterium-containing vacuoles by small interferoninducible guanylate-binding proteins encoded on chromosome 3 (GBP chr3 )-mediated lysis of the vacuoles. In vivo studies have clearly shown that caspase-11 À/À mice are more resistant to endotoxic septic shock by excessive LPS challenge. Given the evidence, activation of caspase-11 non-canonical inflammasomes by intracellular LPS is distinct from canonical inflammasome activation and provides a new paradigm in macrophagemediated inflammatory responses.

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“…g) and the secretion of IL‐1 β and IL‐18 (Fig. j) by generating pores within the cell membrane during the caspase‐11 non‐canonical inflammasome response in macrophages …”

Section: Non‐canonical Inflammasome Activation During Inflammatory Rementioning

confidence: 99%

Caspase‐11 non‐canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage‐mediated inflammatory responses

2017

Immunology

189

216

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“…Recently, a family of proteins named Gasdermins have emerged as key mediators of inflammatory caspases‐mediated cells death . Caspase‐1 or caspase‐11 have been shown to cleave Gasdermin D (GSDMD).…”

Section: Aim2 Activation Leads To Inflammasome Assemlymentioning

confidence: 99%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

290

205

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Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity.

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“…These inflammatory caspases then cleave the N-terminus of Gasdermin D (GSDMD), releasing it from the autoinhibitory C domain. Activated GSDMD-N then translocates and binds to lipids in the plasma membrane forming pores, leading to cell death [53,54,55]. This has been viewed as a way of releasing cytokines from macrophages in the context of infection.…”

Section: Cell Death In Drug-induced Liver Injury (Dili)mentioning

confidence: 99%

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Iorga

Dara

Kaplowitz

2017

IJMS

232

133

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Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

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Recent Insights into the Molecular Mechanisms Underlying Pyroptosis and Gasdermin Family Functions

Cited by 318 publications

References 83 publications

Caspase‐11 non‐canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage‐mediated inflammatory responses

Caspase‐11 non‐canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage‐mediated inflammatory responses

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

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