Toward targeting inflammasomes: insights into their regulation and activation

Christgen, Shelbi; Place, David E.; Kanneganti, Thirumala‐Devi

doi:10.1038/s41422-020-0295-8

Cited by 191 publications

(132 citation statements)

References 191 publications

(215 reference statements)

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“…These data suggest that there might be NLRP3 independent pathways to produce IL1β and IL18 in DGalN/LPS model. This speculation is supported by the previous demonstration that IL1β and IL18 processes are also mediated by other in ammasomes [43]. Our results showed that NLRP2 and AIM2 were upregulated in the liver of DGalN/LPS treated WT mice.…”

Section: Discussionsupporting

confidence: 88%

NLRP3 is dispensable for D-galactosamine/Lipopolysaccharide-induced fulminant hepatitis

Zhang

Tao

Wang

et al. 2020

Preprint

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Background: The NOD-like receptor family protein 3 (NLRP3) inflammasome is involved in the progression of liver inflammation. NLRP3 inactivation has been shown to protect mice against multiple types of experimental liver injury. However, it is unclear whether NLRP3 contributes to D-Galactosamine (DGalN) plus lipopolysaccharide (LPS) induced fatal hepatitis. This study aims to examine the function of NLRP3 inflammasome in DGalN/LPS induced acute liver failure.Method: The expression of inflammasomes was detected by quantitative PCR. Wild type (WT) mice and NLRP3 knockout mice were given an intraperitoneal injection of DGalN plus LPS. Liver damage was examined at 6 h post DGalN/LPS administration by histological analysis and serum aminotransferases measurement. Hepatocyte apoptosis and pyroptosis was detected with TUNEL assay, immunohistochemistry (IHC) staining, and western blot. Hepatic macrophages (F4/80+) and neutrophils (Ly6G+) were analyzed by IHC staining. The proinflammatory cytokines levels in serum and liver were examined using cytometric bead array and quantitative PCR. Hepatic IL1β level was further detected by western blot.Result: The hepatic NLRP3 activity was upregulated in WT mice treated with DGalN/LPS. Nlrp3−/− and WT mice showed similar mortality against lethal dose of DGalN/LPS. Serum aminotransferases levels and liver necrosis area of Nlrp3−/− mice did not differ from that in WT mice after DGalN/LPS injection. The numbers of liver TUNEL positive cells and cleaved caspase3 positive hepatocytes were comparable between Nlrp3−/− and WT mice. The hepatic GSDMDNterm peptide production also showed no difference between Nlrp3−/− and WT mice. Mice treated with DGalN/LPS displayed significantly increased numbers of intrahepatic F4/80+ cells and Ly6G+ cells, but the cell numbers in Nlrp3−/− mice livers were similar to those in WT mice. Consistently, serum and hepatic TNFα, IL6, and MCP-1 levels were similar between Nlrp3−/− and WT mice upon DGalN/LPS administration, but serum IL1β and hepatic mature IL1β level in Nlrp3−/− mice was reduced.Conclusions: NLRP3 ablation does not protect mice from DGalN/LPS induced acute liver failure, nor affect hepatocyte apoptosis and pyroptosis. Deficiency of NLRP3 has a limited effect on intrahepatic inflammatory response induced by DGalN/LPS treatment. NLRP3 inflammasome does not appear to be a major contributor to DGalN/LPS induced fatal hepatitis.

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Section: Discussionsupporting

confidence: 88%

NLRP3 is dispensable for D-galactosamine/Lipopolysaccharide-induced fulminant hepatitis

Zhang

Tao

Wang

et al. 2020

Preprint

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“…This leakage eventually damages mitochondria further increasing ROS production, which can trigger inflammasome activation [ 143 , 144 ] ( Figure 4 ). Inflammasomes are important cytosolic signaling platform, mediating caspase-1 activation and the secretion of pro-inflammatory cytokines including IL-1β and IL-18 [ 145 ]. The best-studied inflammasome is the Nod-like receptor family, pyrin domain-containing 3 (NLRP3)-inflammasome, which can be activated by multiple stimuli, including membrane damage ( Figure 4 ).…”

Section: Membrane Damage Recognition and Cell Responsementioning

confidence: 99%

“…A recent study showed that Gal8 recruited to damaged lysosomes binds to TRIM16, which sequesters processed IL-1β ( Figure 4 ). TRIM16 coordinates autophagosome assembly and transfers IL-1β to secretory autophagic vesicles to enhance IL-1β secretion [ 105 , 145 ]. If Gal3/Trim16 has a similar role is not known.…”

Section: Membrane Damage Recognition and Cell Responsementioning

confidence: 99%

“Repair Me if You Can”: Membrane Damage, Response, and Control from the Viral Perspective

Daussy

Wodrich

2020

Cells

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Cells are constantly challenged by pathogens (bacteria, virus, and fungi), and protein aggregates or chemicals, which can provoke membrane damage at the plasma membrane or within the endo-lysosomal compartments. Detection of endo-lysosomal rupture depends on a family of sugar-binding lectins, known as galectins, which sense the abnormal exposure of glycans to the cytoplasm upon membrane damage. Galectins in conjunction with other factors orchestrate specific membrane damage responses such as the recruitment of the endosomal sorting complex required for transport (ESCRT) machinery to either repair damaged membranes or the activation of autophagy to remove membrane remnants. If not controlled, membrane damage causes the release of harmful components including protons, reactive oxygen species, or cathepsins that will elicit inflammation. In this review, we provide an overview of current knowledge on membrane damage and cellular responses. In particular, we focus on the endo-lysosomal damage triggered by non-enveloped viruses (such as adenovirus) and discuss viral strategies to control the cellular membrane damage response. Finally, we debate the link between autophagy and inflammation in this context and discuss the possibility that virus induced autophagy upon entry limits inflammation.

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“…The triggering signal (second step) leads to the NLRP3 inflammasome assembly and is provided by a multitude of stimuli, ranging from K + efflux, ROS generation, mitochondrial and lysosomal damage [ 62 ]. Despite the heterogeneity of stimuli listed above, the quick drop of intracellular K + concentration, caused by opening of plasma membrane channels (P2X7R included) and responsible of the assembly of the fully active NLRP3 complex (NLRP3-ASC-NEK7-Caspase-1), is considered the most common event for inflammasome triggering [ 65 , 66 , 67 ] ( Figure 1 ).…”

Section: P2x7r In Skeletal Muscle Cells and Muscular Tissue At Stementioning

confidence: 99%

eATP/P2X7R Axis: An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases

Panicucci

Raffaghello

Bruzzone

et al. 2020

IJMS

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In muscle ATP is primarily known for its function as an energy source and as a mediator of the “excitation-transcription” process, which guarantees muscle plasticity in response to environmental stimuli. When quickly released in massive concentrations in the extracellular space as in presence of muscle membrane damage, ATP acts as a damage-associated molecular pattern molecule (DAMP). In experimental murine models of muscular dystrophies characterized by membrane instability, blockade of eATP/P2X7 receptor (R) purinergic signaling delayed the progression of the dystrophic phenotype dampening the local inflammatory response and inducing Foxp3+ T Regulatory lymphocytes. These discoveries highlighted the relevance of ATP as a harbinger of immune-tissue damage in muscular genetic diseases. Given the interactions between the immune system and muscle regeneration, the comprehension of ATP/purinerigic pathway articulated organization in muscle cells has become of extreme interest. This review explores ATP release, metabolism, feedback control and cross-talk with members of muscle inflammasome in the context of muscular dystrophies.

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Toward targeting inflammasomes: insights into their regulation and activation

Cited by 191 publications

References 191 publications

NLRP3 is dispensable for D-galactosamine/Lipopolysaccharide-induced fulminant hepatitis

NLRP3 is dispensable for D-galactosamine/Lipopolysaccharide-induced fulminant hepatitis

“Repair Me if You Can”: Membrane Damage, Response, and Control from the Viral Perspective

eATP/P2X7R Axis: An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases

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