Role of the Inflammasome in Liver Disease

Ribeiro, Marcelle; Szabó, Gyöngyi

doi:10.1146/annurev-pathmechdis-032521-102529

Cited by 135 publications

(96 citation statements)

References 120 publications

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“…Increasing studies have shown that cold exposure can result in liver damage [ 21 , 22 ]. In addition, the involvement of pyroptosis, inflammasomes and oxidative stress in the pro-inflammatory response is observed in many liver diseases, such as metabolic-associated fatty liver disease, nonalcoholic fatty liver disease and alcohol-associated liver disease [ 23 , 24 ]. However, very few studies have revealed pyroptosis’s underlying mechanisms of cold stress in liver damage.…”

Section: Discussionmentioning

confidence: 99%

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

et al. 2022

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The body needs to generate heat to ensure basic life activities when exposed to cold temperatures. The liver, as the largest glycogen storage organ in the body and main heat-producing organ at rest, may play a role in chronic cold exposure. Recent studies suggested that pyroptosis plays a crucial role in liver diseases. However, the role of pyroptosis in cold stress-induced liver injury is not clear. Hence, in this study, we attempted to investigate the effects of chronic cold exposure on liver function, apoptosis, oxidative stress and inflammation in mice by establishing a mouse model of chronic cold exposure, and to investigate whether pyroptosis pathways are involved in the process of chronic cold exposure. In vivo, our results show that inflammatory cell infiltration and other pathological changes in liver cells and the activity of liver enzyme evidently increased in the serum and liver of cold-exposed mice, suggesting cold stress may result in liver injury. Remarkably, increased expression of heat shock protein 70 (HSP70) and HSP90 proteins proved the cold stress model is successfully constructed. Then, elevated levels of apoptosis, inflammation, oxidative stress and pyroptosis related proteins and mRNAs, such as cysteinyl aspartate specific proteinase-3 (Caspase-3), inducible nitric oxide synthase (iNOS), nuclear factor erythroid2-related factor 2 (Nrf2) and gasdermins D (GSDMD), confirmed that cold exposure activated apoptosis, oxidative stress and pyroptosis, and released inflammation cytokines. Meanwhile, in vitro, we got similar results as in vivo. Further, adding an NLR family pyrin domain containing 3 (NLRP3) inhibitors found that suppression expression of NLRP3 results in the essential proteins of pyroptosis and antioxidant evidently reduced, and adding GSDMD inhibitor found that suppression expression of GSDMD accompanies with the level of Nrf2 and heme oxygenase-1 (HO-1) obviously reduced. In summary, these findings provide a new understanding of the underlying mechanisms of the cold stress response, which can inform the development of new strategies to combat the effects of hypothermia.

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Section: Discussionmentioning

confidence: 99%

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

et al. 2022

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“…Previous studies have revealed that dhBBR reduces inflammation via an NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-related mechanism, which likely reduces the release of caspase-1,apoptosis-associated speck-like protein (ASC) and IL-1β to inhibit pyroptotic cell death, which is a form of programmed cell death that occurs in liver fibrosis. ( Xu et al, 2021a ; de Carvalho Ribeiro and Szabo, 2021 ). dhBBR may even have better anti-sclerotic effects than BBR.…”

Section: Anti-fibrosis Effects Of Berberine In the Livermentioning

confidence: 99%

Therapeutic Effects of Berberine on Liver Fibrosis are associated With Lipid Metabolism and Intestinal Flora

et al. 2022

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Liver cirrhosis is a form of liver fibrosis resulting from chronic hepatitis caused by various liver diseases, such as viral hepatitis, alcoholic liver damage, nonalcoholic steatohepatitis, autoimmune liver disease, and by parasitic diseases such as schistosomiasis. Liver fibrosis is the common pathological base and precursors of cirrhosis. Inflammation and disorders of lipid metabolism are key drivers in liver fibrosis. Studies have determined that parts of the arachidonic acid pathway, such as its metabolic enzymes and biologically active products, are hallmarks of inflammation, and that aberrant peroxisome proliferator-activated receptor gamma (PPARγ)-mediated regulation causes disorders of lipid metabolism. However, despite the ongoing research focus on delineating the mechanisms of liver fibrosis that underpin various chronic liver diseases, effective clinical treatments have yet to be developed. Berberine (BBR) is an isoquinoline alkaloid with multiple biological activities, such as anti-inflammatory, anti-bacterial, anti-cancer, and anti-hyperlipidemic activities. Many studies have also found that BBR acts via multiple pathways to alleviate liver fibrosis. Furthermore, the absorption of BBR is increased by nitroreductase-containing intestinal flora, and is strengthened via crosstalk with bile acid metabolism. This improves the oral bioavailability of BBR, thereby enhancing its clinical utility. The production of butyrate by intestinal anaerobic bacteria is dramatically increased by BBR, thereby amplifying butyrate-mediated alleviation of liver fibrosis. In this review, we discuss the effects of BBR on liver fibrosis and lipid metabolism, particularly the metabolism of arachidonic acid, and highlight the potential mechanisms by which BBR relieves liver fibrosis through lipid metabolism related and intestinal flora related pathways. We hope that this review will provide insights on the BBR-based treatment of liver cirrhosis and related research in this area, and we encourage further studies that increase the ability of BBR to enhance liver health.

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“…In the liver, pathogen‐associated molecular patterns (PAMPs, such as gut‐derived LPS) and DAMPs (e.g. ATP) released from damaged hepatocytes in response to ethanol induce a local sterile inflammatory response that involves activation of inflammasomes especially NLRP3 (de Carvalho Ribeiro & Szabo, 2022; Szabo, 2017). NLRP3 activation requires a two‐step process.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation, consisting mainly of neutrophilic infiltrates, is one of the main characteristics of ASH development (Bertola, 2020). Current studies on the inflammatory response in ASH have mostly (de Carvalho Ribeiro & Szabo, 2022;Szabo, 2017). NLRP3 activation requires a two-step process.…”

Section: Discussionmentioning

confidence: 99%

Modulation of interleukin‐36 based inflammatory feedback loop through the hepatocyte‐derived IL‐36R‐P2X7R axis improves steatosis in alcoholic steatohepatitis

Shang

Yang

et al. 2022

British J Pharmacology

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Background and Purpose: Interleukin-36 is induced by proinflammatory cytokines and promotes inflammatory responses, creating an IL-36-based inflammation loop.Although hepatocytes, produce IL-36 responses to drug-induced liver injury, little is known about the mechanistic role of IL-36 signalling during the progression of alcoholic steatohepatitis (ASH). Regarding IL-36/IL-36R and P2X7R coregulating the inflammatory response, we elucidated that modulation of IL-36R-P2X7R-TLR axis affected hepatocyte steatosis as well as the IL-36-based inflammatory feedback loop that accompanies the onset of ASH.Experimental Approach: C57BL/6J mice were subjected to either chronic-plus-binge ethanol feeding or acute gavage with multiple doses of ethanol to establish ASH, followed by pharmacological inhibition or genetic silencing of IL-36R and P2X7R.

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Role of the Inflammasome in Liver Disease

Cited by 135 publications

References 120 publications

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

Cold Stress Induced Liver Injury of Mice through Activated NLRP3/Caspase-1/GSDMD Pyroptosis Signaling Pathway

Therapeutic Effects of Berberine on Liver Fibrosis are associated With Lipid Metabolism and Intestinal Flora

Modulation of interleukin‐36 based inflammatory feedback loop through the hepatocyte‐derived IL‐36R‐P2X7R axis improves steatosis in alcoholic steatohepatitis

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