scholarly journals Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322509
Author(s):  
Eun Hee Koh ◽  
Ji Eun Yoon ◽  
Myoung Seok Ko ◽  
Jaechan Leem ◽  
Ji-Young Yun ◽  
...  
Keyword(s):  
Mouse Models ◽  
Free Cholesterol ◽  
High Cholesterol Diet ◽  
Inflammasome Activation ◽  
Hepatic Expression ◽  
Sphingomyelin Synthase ◽  
Alcoholic Steatohepatitis ◽  
Pyrin Domain ◽  
Hepatocyte Injury

ObjectiveLipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.DesignWild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).ResultsHFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.ConclusionSMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.

Role of the Inflammasome in Liver Disease

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Marcelle de Carvalho Ribeiro ◽  
Gyongyi Szabo
Keyword(s):  
Liver Disease ◽  
Liver Diseases ◽  
Annual Review ◽  
Publication Date ◽  
Inflammasome Activation ◽  
Proinflammatory Response ◽  
Nonalcoholic Fatty Liver ◽  
Pyrin Domain ◽  
Different Types

The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on ( a) signals and mechanisms of inflammasome activation, ( b) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and ( c) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Role of Histone Deacetylase 9 in the Therapeutic Effects of Astaxanthin on Non-Alcoholic Steatohepatitis

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1257-1257
Author(s):  
Siqi Hu ◽  
Hyunju Kang ◽  
Hyungryun Jang ◽  
Minkyung Bae ◽  
Mi-Bo Kim ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Control Diet ◽  
Genotypic Differences ◽  
Therapeutic Effects ◽  
Inflammatory Genes ◽  
Female Mice ◽  
Hepatic Expression ◽  
Alcoholic Steatohepatitis ◽  
Histone Deacetylase 9

Abstract Objectives The objectives of this study were to determine the role of histone deacetylase 9 (HDAC9) in the development of non-alcoholic steatohepatitis (NASH); and to evaluate the therapeutic effects of astaxanthin (ASTX), a xanthophyll carotenoid, on NASH via the modulation of HDAC9 in vivo. Methods Eight-week-old male and female wild-type (WT) and global Hdac9 knockout (KO) mice (n = 30/sex/genotype) were fed a high-fat/high-sucrose/high-cholesterol (HFHSHC) diet for 20 weeks to induce NASH. Subsequently, subsets of WT (n = 10/sex) and KO (n = 10/sex) mice were sacrificed to examine NASH features and served as baseline controls. The rest of the mice were randomly assigned into two diet groups for another 10 weeks: One continued on the HFHSHC diet, while the other group was fed an HFHSHC containing 0.03% ASTX (w/w). Results After 20 weeks on the HFHSHC diet, male KO mice had lower liver weights and triglycerides than WT, but no genotypic differences were observed in the female. Male KO mice showed less liver steatosis and fibrosis with significant decreases in the hepatic expression of lipogenic genes than male WT mice, but Hdac9 deletion did not inhibit NASH development in female mice. Compared with male KO baseline controls, consumption of control diet for an additional 10 week increased hepatic expression of lipogenic and pro-inflammatory genes in male KO mice, losing the beneficial effect of Hdac9 deletion shown at week 20 on the HFHSHC diet. However, the ASTX diet abrogated the induction. There were no significant differences in hepatic lipid contents and histological features of NASH between any genotypes regardless of ASTX supplementation. Also, additional control diet feeding did not induce any changes in hepatic gene expression in female mice, compared with those on the ASTX diet. Conclusions Hdac9 deletion protected male, but not female, mice from diet-induced hepatic steatosis and fibrosis, which may be attributable to decreased lipogenesis in the liver. However, the protection did not exist when liver damages progressed. Hdac9 deletion or ASTX alone did not alleviate the liver damage progression, but they together inhibited the induction of lipogenic and pro-inflammatory genes in the liver of male mice, indicating that they may have synergistic effects on ameliorating NASH progression. Funding Sources The study was supported by National Institutes of Health.

scholarly journals Reversal of Endothelial Extracellular Vesicle-Induced Smooth Muscle Phenotype Transition by Hypercholesterolemia Stimulation: Role of NLRP3 Inflammasome Activation

2020 ◽  
Vol 8 ◽  
Author(s):  
Xinxu Yuan ◽  
Owais M. Bhat ◽  
Arun Samidurai ◽  
Anindita Das ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Nlrp3 Inflammasome ◽  
Vascular Endothelial Cells ◽  
Gene Knockout ◽  
Cell Communication ◽  
Extracellular Vesicle ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Phenotype Transition

Recent studies reported that vascular endothelial cells (ECs) secrete NLR family pyrin domain-containing 3 (NLRP3) inflammasome products such as interleukin-1β (IL-1β) via extracellular vesicles (EVs) under various pathological conditions. EVs represent one of the critical mechanisms mediating the cell-to-cell communication between ECs and vascular smooth muscle cells (VSMCs). However, whether or not the inflammasome-dependent EVs directly participate in the regulation of VSMC function remains unknown. In the present study, we found that in cultured carotid ECs, atherogenic stimulation by oxysterol 7-ketocholesterol (7-Ket) induced NLRP3 inflammasome formation and activation, reduced lysosome-multivesicular bodies (MVBs) fusion, and increased secretion of EVs that contain inflammasome product IL-1β. These EC-derived IL-1β-containing EVs promoted synthetic phenotype transition of co-cultured VSMCs, whereas EVs from unstimulated ECs have the opposite effects. Moreover, acid ceramidase (AC) deficiency or lysosome inhibition further exaggerated the 7-Ket-induced release of IL-1β-containing EVs in ECs. Using a Western diet (WD)-induced hypercholesterolemia mouse model, we found that endothelial-specific AC gene knockout mice (Asah1fl/fl/ECCre) exhibited augmented WD-induced EV secretion with IL-1β and more significantly decreased the interaction of MVBs with lysosomes in the carotid arterial wall compared to their wild-type littermates (WT/WT). The endothelial AC deficiency in Asah1fl/fl/ECCre mice also resulted in enhanced VSMC phenotype transition and accelerated neointima formation. Together, these results suggest that NLRP3 inflammasome-dependent IL-1β production during hypercholesterolemia promotes VSMC phenotype transition to synthetic status via EV machinery, which is controlled by lysosomal AC activity. Our findings provide novel mechanistic insights into understanding the pathogenic role of endothelial NLRP3 inflammasome in vascular injury through EV-mediated EC-to-VSMC regulation.

scholarly journals MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs

2021 ◽  
Vol 22 (22) ◽  
pp. 12413
Author(s):  
Shuang Ge ◽  
Wei Yang ◽  
Haiqiang Chen ◽  
Qi Yuan ◽  
Shi Liu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Cell ◽  
Myeloid Cells ◽  
Inflammasome Activation ◽  
Potential Candidate ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Candidate Target

Chronic liver disease mediated by the activation of hepatic stellate cells (HSCs) leads to liver fibrosis. The signal adaptor MyD88 of Toll-like receptor (TLR) signaling is involved during the progression of liver fibrosis. However, the specific role of MyD88 in myeloid cells in liver fibrosis has not been thoroughly investigated. In this study, we used a carbon tetrachloride (CCl4)-induced mouse fibrosis model in which MyD88 was selectively depleted in myeloid cells. MyD88 deficiency in myeloid cells attenuated liver fibrosis in mice and decreased inflammatory cell infiltration. Furthermore, deficiency of MyD88 in macrophages inhibits the secretion of CXC motif chemokine 2 (CXCL2), which restrains the activation of HSCs characterized by NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation. Moreover, targeting CXCL2 by CXCR2 inhibitors attenuated the activation of HSCs and reduced liver fibrosis. Thus, MyD88 may represent a potential candidate target for the prevention and treatment of liver fibrosis.

NLRP3 inflammasome is involved in uterine activation for labor at term and preterm

Reproduction ◽  
2021 ◽  
Vol 162 (6) ◽  
pp. 449-460
Author(s):  
Zixi Chen ◽  
Yali Shan ◽  
Xingji You ◽  
Hang Gu ◽  
Chen Xu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Pregnant Mice ◽  
Labor Onset

The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases. We sought to investigate the role of NLRP3 inflammasome in uterine activation for labor at term and preterm. We found that NLRP3 inflammasome was activated in the myometrium tissues obtained from the pregnant women undergoing labor at term (TL) compared with those not undergoing labor (TNL) at term. NLRP3 inflammasome was also activated in amnion and chorion-deciduas in TL and preterm labor (PTL) groups. In the mouse model, uterine NLRP3 inflammasome and nuclear factor kappaB (NF-κB) were activated toward term and during labor. Treatment of pregnant mice with lipopolysaccharide (LPS) and RU38486 induced preterm birth (PTB) and also promoted uterine NLRP3 inflammasome and NF-κB activation. Treatment of pregnant mice with NLRP3 inflammasome inhibitor BAY11-7082 and MCC950 delayed the onset of labor and suppressed NLRP3 inflammasome and NF-κB activation in uterus. MCC950 postponed labor onset of the mice with LPS and RU38486 treatment and inhibited NLRP3 inflammasome activation in uterus. Our data provide the evidence that NLRP3 inflammasome is involved in uterine activation for labor onset in term and PTB in humans and mouse model.

scholarly journals Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

Gut ◽  
2018 ◽  
Vol 67 (5) ◽  
pp. 963-972 ◽  
Author(s):  
Samar H Ibrahim ◽  
Petra Hirsova ◽  
Gregory J Gores
Keyword(s):  
Immune Cell ◽  
Innate Immune ◽  
Liver Inflammation ◽  
Hepatocellular Injury ◽  
Alcoholic Fatty Liver ◽  
Disease Biomarkers ◽  
Alcoholic Steatohepatitis ◽  
Hepatocyte Injury ◽  
Alcoholic Fatty Liver Disease

A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed non-alcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation.

scholarly journals Protective Role of Trans-chalcone against the Progression from Simple Steatosis to Non-alcoholic Steatohepatitis: Regulation of miR-122, 21, 34a, and 451

2021 ◽  
Author(s):  
Elham Karimi-Sales ◽  
Sajad Jeddi ◽  
Abbas Ebrahimi-Kalan ◽  
Mohammad Reza Alipour
Keyword(s):  
Tween 80 ◽  
Protective Role ◽  
Male Rats ◽  
Inflammatory Disorder ◽  
Expression Levels ◽  
Hepatic Expression ◽  
Alcoholic Steatohepatitis ◽  
Aggressive Form ◽  
Induced Changes

Purpose: Non-alcoholic steatohepatitis (NASH) is an inflammatory disorder and an aggressive form of fatty liver disease. Certain microRNAs, including miR-122, 21, 34a, and 451, are involved in the transition from steatosis to NASH. This study examined how trans-chalcone (the core of chalcone derivatives) affects NAFLD progression by regulating miRNAs. Methods: Male rats were divided into three groups (n = 7/group) as follows: control, rats were gavaged with 10% tween 80 (for two weeks); NASH, rats were gavaged with a high-fat liquid diet (HFD; for six weeks) and 10% tween 80 (for two weeks); NASH + Chal, rats were gavaged with the HFD (for six weeks) and trans-chalcone (for two weeks). Hepatic expression levels of miR-122, 21, 34a, and 451 were determined. Results: trans-Chalcone reversed histological abnormalities, reduced liver injury markers, and attenuated insulin resistance in HFD-fed rats. In the liver, HFD-induced NASH increased the expression level of miR-34a and decreased expression levels of miR-122, 21, and 451. However, trans-chalcone inhibited HFD-induced changes in expression levels of these miRNAs. Conclusion: trans-Chalcone could inhibit the transition from steatosis to NASH through the modulation of miR-122, 21, 34a, and 451 expression levels in the liver.

scholarly journals A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly

2016 ◽  
Vol 213 (5) ◽  
pp. 771-790 ◽  
Author(s):  
Florian I. Schmidt ◽  
Alvin Lu ◽  
Jeff W. Chen ◽  
Jianbin Ruan ◽  
Catherine Tang ◽  
...  
Keyword(s):  
Cell Damage ◽  
Antibody Fragment ◽  
Single Domain ◽  
Inflammasome Activation ◽  
Single Domain Antibody ◽  
Pyrin Domain ◽  
Domain Antibody ◽  
First Time

Myeloid cells assemble inflammasomes in response to infection or cell damage; cytosolic sensors activate pro–caspase-1, indirectly for the most part, via the adaptors ASC and NLRC4. This leads to secretion of proinflammatory cytokines and pyroptosis. To explore complex formation under physiological conditions, we generated an alpaca single domain antibody, VHHASC, which specifically recognizes the CARD of human ASC via its type II interface. VHHASC not only impairs ASCCARD interactions in vitro, but also inhibits inflammasome activation in response to NLRP3, AIM2, and NAIP triggers when expressed in living cells, highlighting a role of ASC in all three types of inflammasomes. VHHASC leaves the Pyrin domain of ASC functional and stabilizes a filamentous intermediate of inflammasome activation. Incorporation of VHHASC-EGFP into these structures allowed the visualization of endogenous ASCPYD filaments for the first time. These data revealed that cross-linking of ASCPYD filaments via ASCCARD mediates the assembly of ASC foci.

scholarly journals Galectin-9 regulates serum amyloid A-induced inflammasome activation in human neutrophils

2020 ◽  
Author(s):  
Jumpei Temmoku ◽  
Yuya Fujita ◽  
Haruki Matsumoto ◽  
Naoki Matsuoka ◽  
Tomoyuki i Asano ◽  
...  
Keyword(s):  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Negative Regulator ◽  
Human Neutrophils ◽  
Inflammasome Activation ◽  
Inhibitory Interaction ◽  
Amyloid A ◽  
Pyrin Domain ◽  
Elisa Data

Abstract Objective The Nod-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome plays roles in host defense and the development of autoinflammation. Galection-9 (Gal-9), one of the β-galactoside binding lectins, plays important regulatory roles in autoimmune diseases. T cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3)/Gal-9 inhibitory interaction has been proposed in innate immune system. We investigate the role of Galectin-9 (Gal-9) on serum amyloid A (SAA)-induced inflammasome activation and IL-1β processing by human neutrophils. Results SAA stimulation induced the release of cleavage of IL-1β (p17) from neutrophils suggesting that SAA induces the inflammasome activation and subsequent processing of pro-IL-1β. ELISA data demonstrated that SAA stimulation also induced cleaved caspase-1 (p20) secretion from human neutrophils, and this release was suppressed by Gal-9 pretreatment. Gal-9 pretreatment diminished the SAA-induced cleaved IL-1β secretion, however, did not affect SAA-induced pro-IL-1β secretion from neutrophils. Furthermore, Gal-9 pretreatment suppressed SAA-induced intracellular accumulation of cleaved IL-1β, suggesting that Gal-9 functions as a negative regulator of SAA-induced inflammasome activation and may be a potential therapeutic target for the treatment of autoinflammatory disorders.

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