Dynamics of in vivo ASC speck formation

Kuri, Paola; Schieber, Nicole L.; Thumberger, Thomas; Wittbrodt, Joachim; Schwab, Yannick; Leptin, Maria

doi:10.1083/jcb.201703103

Cited by 59 publications

(87 citation statements)

References 86 publications

(133 reference statements)

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“…Extracellular ASC specks were detected in tissues from patients and mice with chronic respiratory diseases, or systemically in the sera of patients with autoinflammatory diseases . These findings consolidate several earlier speculations, and extracellular ASC specks have now been observed in different studies, in vitro and in vivo . ASC specks were shown to be released by inflammasome‐activated macrophages and associated with ectopically delivered POP1, which prevented their inflammatory properties in recipient cells, or after their injection into mice .…”

Section: Extracellular Asc Specks—mechanisms Of Release and Uptakesupporting

confidence: 79%

“…In vitro, phagocytosis of ASC specks provoked further inflammasome activation and IL‐1β release by macrophages . In contrast, zebrafish macrophages removed and degraded extracellular ASC specks, and did not recruit additional ASC molecules, suggesting that these cells have a role in the resolution of inflammation . Whether these findings can be recapitulated in mammalian cells, remains to be shown.…”

Section: Regulation Of Asc Speck Release and Their Clearance From Thementioning

confidence: 97%

“…This indicates that phosphorylation of ASC CARD is necessary for cross‐linking of ASC PYD filaments, a mechanism that allows precise control over ASC speck assembly, and perhaps the degree of cross‐linking. Of note, the Y136 phosphorylation site is conserved in zebrafish ASC, and its mutation to phenylalanine led to filamentous ASC‐mKate2 structures in the larvae upon activation . It is unknown what fraction of ASC CARD Y146 is phosphorylated and whether this differentially affects interactions with other ASC filaments or caspase‐1.…”

Section: Assembly and Regulation Of Asc Specksmentioning

confidence: 99%

“…Given the enormous “operating expenses” of ASC specks composed of hundreds of monomers and the conservation of ASC specks from fish to mammals, it is likely that ASC specks serve an important function that goes beyond maximizing caspase‐1 activation. The intricate, likely regulated structure of this SMOC may form a reaction space or “quasi‐organelle” that compartmentalizes biological functions from the rest of the cytosol.…”

Section: Function Of Asc Specksmentioning

confidence: 99%

“…In two independent studies, mice expressing a fluorescent ASC‐reporter construct revealed the release of ASC specks into the extracellular space and their accumulation in tissues upon challenge with inflammasome activators, bacterial, or viral infection . More recently, a study describing the generation of a Zebrafish ASC‐reporter model confirmed the release of ASC specks by keratinocytes, and showed their uptake by surrounding immune cells . Nevertheless, the mechanisms by which ASC specks are released, and the immunological relevance of their release remain largely unexplored.…”

Section: Extracellular Asc Specks—mechanisms Of Release and Uptakementioning

confidence: 99%

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The intra‐ and extracellular functions of ASC specks

Franklin

Latz

Schmidt

2017

Immunological Reviews

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Inflammasomes are the central signaling hubs of the inflammatory response. They process cytosolic evidence of infection, cell damage, or metabolic disturbances, and elicit a pro-inflammatory response mediated by members of the interleukin-1 family of cytokines and pyroptotoic cell death. On the molecular level, this is accomplished by the sensor-nucleated recruitment and oligomerization of the adapter protein ASC. Once a tunable threshold is reached, cooperative assembly of ASC into linear filaments and their condensation into macromolecular ASC specks promotes an all-or-none response. These structures are highly regulated and provide a unique signaling platform or compartment to control the activity of caspase-1 and likely other effectors. Emerging evidence indicates that ASC specks are also released from inflammasome-activated cells and accumulate in inflamed tissues, where they can continue to mature cytokines or be internalized by surrounding cells to further nucleate ASC specks in their cytosol. Little is known about the mechanisms governing ASC speck release, uptake, and endosomal escape, as well as its contribution to inflammation and disease. Here, we describe the different outcomes of inflammasome activation and discuss the potential function of extracellular ASC specks. We highlight gaps in our understanding of this central process of inflammation, which may have direct consequences on the modulation of host responses and chronic inflammation.

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Section: Extracellular Asc Specks—mechanisms Of Release and Uptakesupporting

confidence: 79%

Section: Regulation Of Asc Speck Release and Their Clearance From Thementioning

confidence: 97%

Section: Assembly and Regulation Of Asc Specksmentioning

confidence: 99%

Section: Function Of Asc Specksmentioning

confidence: 99%

Section: Extracellular Asc Specks—mechanisms Of Release and Uptakementioning

confidence: 99%

See 3 more Smart Citations

The intra‐ and extracellular functions of ASC specks

Franklin

Latz

Schmidt

2017

Immunological Reviews

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Nanoreporter for Real‐Time Monitoring of Inflammasome Activity and Targeted Therapy

et al. 2023

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Inflammasome activation is associated with a myriad of inflammatory diseases. However, existing methods provides a limited understanding of spatiotemporal kinetics of inflammasome activation, with restricted scope for early detection of associated treatment efficacy. This limitation offers an opportunity for the development of biocompatible in-vivo inflammasome monitoring tools with translational prospects. To achieve this, they report developing a pair of lipid-based nanoparticle systems, a reporter nanoparticle consisting of a caspase-1 activatable probe alone, and a theranostic nanoparticle combining the probe with an inflammasome-inhibiting drug. This biocompatible platform enhances the probe's residence time in circulation by preventing its opsonization and allowing its sustained release over time. Their results demonstrate the specificity of reporter nanoparticles towards caspase-1 activity and provides early-on monitoring of inflammasome activation both in-vitro as well as in-vivo. Additionally, the delivery of disulfiram, an inflammasome-inhibiting drug, along with reporter probe using theranostic nanoparticles enables real-time tracking of treatment efficacy in the gouty-arthritis inflammatory model. In summary, they report an unparalleled pair of the inflammasome-associated reporter and theranostic platforms suited not only for diagnostic applications but can also detect inflammasome-targeted treatment efficiency in real-time. These findings establish two novel, sensitive nanotools for non-invasive evaluation of inflammasome-targeted immunotherapy.

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Evaluation of Nano‐curcumin effects against Tartrazine‐induced abnormalities in liver and kidney histology and other biochemical parameters

Eldesoky

Wabaidur

ALOthman

et al. 2022

Food Science & Nutrition

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In the current study, 40 albino male rats were investigated to evaluate the impact of Nano-curcumin (Nano-CUR) administration against Tartrazine (TZ)-induced variations in kidney and liver histology and their related functions. The liver function biomarkers are (glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyl transaminase (GGT), alkaline phosphatase (ALP), total bilirubin (T. BiLL)), whereas the kidney biomarkers are (creatinine, uric acid, urea, globulin, total protein (TP)), as well as blood parameters of (serum glucose (sGlu), alpha-fetoprotein (AFP), protein Kinase-C (PKC)) and lipid profiles that include (total lipids (TL), triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density L-C (HDL-C), and very-low-density L-C (VLDL-C)). The collected rats were randomly separated into four different groups (G1, G2, G3, and G4) of 10 rats each, where G1 stands for control, G2 for TZ-ingestion, G3 for Nano-CUR-ingestion, and G4 for (TZ + Nano-CUR mix.) ingestion. TZ-ingestion significantly (p < .05) increases the liver function enzymes' activity, total bilirubin and kidney biomarkers (creatinine, urea, uric acid, total protein (TP), globulin (Glu)). Also, TZ-ingestion significantly increased sGlu, PKC, AFP, as well as lipid profiles, while there were significant (p < .05) decreases in HDL-C and albumin (Alb) concentrations compared to control. Histopathological changes in liver, such as dilatation of blood sinusoids and central vein with hemorrhage and necrosis, were observed due to TZ-ingestion. Similarly, TZ-ingestion influenced kidney tissues in terms of tubular dilatation with tubular degeneration, thickened basement membrane, and dilatation of the glomerular capillaries. Markedly, the administration of Nano-CUR significantly decreased liver and kidney function enzymes as well as sGlu, AFP, and PKC, whereas it significantly increased serum Alb and HDL-C levels compared to control and TZ-ingested rats. All values arranged around normal control values. Also, the liver tissue of Nano-CUR-ingested rats showed a normal arrangement of normal blood sinusoids(s), hepatic cords, and hepatocytes as compared to controls.The same results were also found in the section of rat kidney ingested with 2.00 g of | 1345EL-DESOKY Et aL. | INTRODUC TI ONPeople consume various food additives every day, which have both advantages and disadvantages. Food additives have showed an important impact on food sources and provided people delicious, nutritious, and safe foods (Himri et al., 2011). Food additives are classified into six main groups including preservatives, nutritive additives, flavoring, coloring, texturizing, and miscellaneous compounds (Amin & Al-Shehri, 2018). Food colors are added to give a color to a foodstuff and to restore its usual color, which is usually attractive to consumers, especially children. The synthetic food colors are considered as the class of essential foo...

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Dynamics of in vivo ASC speck formation

Abstract: The inflammasome adaptor ASC forms enormous intracellular complexes called specks. Live imaging of endogenous ASC in keratinocytes reveals speck formation dynamics and their lethal effects, as well as macrophages’ engulfment and digestion of the specks left behind by dead cells.

Cited by 59 publications

References 86 publications

The intra‐ and extracellular functions of ASC specks

The intra‐ and extracellular functions of ASC specks

Nanoreporter for Real‐Time Monitoring of Inflammasome Activity and Targeted Therapy

Evaluation of Nano‐curcumin effects against Tartrazine‐induced abnormalities in liver and kidney histology and other biochemical parameters

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