Cell-specific Deletion of NLRP3 Inflammasome Identifies Myeloid Cells as Key Drivers of Liver Inflammation and Fibrosis in Murine Steatohepatitis

Kaufmann, Benedikt; Kui, Lin; Reca, Agustina; Leszczynska, Aleksandra; Kim, Andrea D.; Booshehri, Laela M.; Wree, Alexander; Friess, Helmut; Broderick, Lori; Hoffman, Hal M.; Feldstein, Ariel E.

doi:10.1016/j.jcmgh.2022.06.007

Cited by 27 publications

(23 citation statements)

References 35 publications

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“…Further exploration of this study con rmed that Mettl3 LKO modulated the original immune landscape of the liver by increasing the in ltration of intrahepatic neutrophils (CD11b + /GR-1 high )/monocytes (CD11b + /GR-1 int ), macrophages (CD11b high /F4/80 + ) and CD11c + dendritic cells. Activation of myeloid-derived immune cells in the liver was reported to promote liver in ammation and brosis (41). Moreover, we also discovered that at 12 weeks of age, METTL3 LKO mice developed spontaneous liver brosis (data was not shown).…”

Section: Discussionmentioning

confidence: 77%

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Wang

Yang

et al. 2023

Preprint

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Background Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related mortality, ranking third in this regard. The epigenetic regulation of RNA N6-methyladenosine (m6A) modification in HCC has garnered considerable attention. This study utilized bioinformatics analysis and biologically engineered mice models to explore the immune and prognostic role of m6A modification in HCC. Methods We systematically analyzed genetic alterations, expression patterns, signaling pathways, prognostic features, and immunotherapy efficacy of the 21 m6A regulators in HCC as obtained from the Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO, GSE14520, GSE76427), and International Cancer Genome Consortium (IGCG) database; Unsupervised clustering, gene set variation analysis (GSVA), LASSO-COX regression, multivariate Cox regression, Nomogram, receiver operating characteristic (ROC) analysis, TIMER 2.0 and ImmuCellAI were used to perform the above analysis. Our analysis was verified with Mettl3F/FAlbumin-cre (liver-specific knockout, LKO) mice to establish a chemo-induced HCC model. The tumor immune microenvironment was analyzed with immunohistochemistry, immunofluorescence staining, and flow cytometry. Results The genetic alteration of the m6A modification gene set exhibited a correlation with reduced progression-free survival, diminished abundance of macrophage cells, and a lower score for immune cell infiltration. The cluster characterized by lower expression of the m6A gene set was linked to a more favorable overall survival (OS) and immune signaling, including IL2-STAT5, IL6-STAT3, IFN-gamma, and IFN-alpha signaling. Notably, the cluster with higher expression of m6A was associated with a higher homologous recombination deficiency (HRD) score and tumor mutational burden (TMB) score. Results of LASSO COX and the nomogram model underscored the significant contribution of METTL3 in the prognosis and ICB therapy of HCC. The results of Mettl3 LKO mice confirmed that Mettl3 LKO acted as a "rheostat" in the progression of HCC by regulating the mouse liver's myeloid-related innate and adaptive immune landscape. Conclusions In this study, we characterized the genetic, immune, and clinic landscape of the m6A gene set in HCC development and unveiled METTL3 as a molecular biomarker in epigenetic-related progress and ICB therapy of HCC from both informatics database analysis and engineered mice model.

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Section: Discussionmentioning

confidence: 77%

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Wang

Yang

et al. 2023

Preprint

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“…Additionally, it can be found in the cytoplasm of HSCs and can be triggered by several different pathogens, including S. mansoni , E. coli , and S. japonicum (Chen et al 2019; Meng et al 2016). The activation of caspase-1 and the subsequent release of IL-1β are made possible by the NLRP3 inflammasome, which is crucial in the development of hepatic fibrosis and inflammation (Kaufmann et al 2022). In addition, collagen deposition and NLRP3 activation in primary human hepatocytes results in pyroptotic cell death (Gaul et al 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Auranofin was also shown by Kim et al (2021) to considerably slow the progression of fibrosis in a thioacetamide- or carbon tetrachloride-induced fibrotic liver (Kim et al 2021). Additionally, Kaufmann et al (2022) found that the production of pro-inflammatory and pro-fibrotic cytokines as well as the onset of liver inflammation and fibrosis depends on the activation of the NLRP3 inflammasome complex in myeloid cells (Kaufmann et al 2022). Production of cytokines, such as IL-1β, may occur after the activation of the NLRP3 inflammasome in KCs.…”

Section: Discussionmentioning

confidence: 99%

Auranofin attenuates Schistosoma mansoni egg-induced liver granuloma and fibrosis in mice

Atia,

Abou-Hussien,

Sweed

et al. 2023

J. Helminthol.

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Schistosomiasis is a serious tropical disease. Despite extensive research into the etiology of liver fibrosis, effective therapeutic options remain limited. This study aims to assess the effectiveness of auranofin in treating hepatic granuloma and fibrogenesis produced by Schistosoma (S.) mansoni eggs. Auranofin is a gold complex that contains thioglucose tetraacetate and triethylphosphine. Eighty BALB/c male mice were divided into four groups (n=20/group): negative control (GI), positive control (GII), and early (GIII) and late (GIV) treatment groups with oral auranofin according to beginning of treatment 4th week and 6th week post-infection. Mice were infected subcutaneously in a dose of 60±10 cercariae/mouse. Worm counts, egg loads, and oogram patterns were determined. Biochemical, histological, and immunostaining of interleukin-1β (IL-1β), Sirtuin 3 (SIRT3), and smooth muscle actin (SMA) were assessed. GIII showed a significant decrease in the total S. mansoni worm burden and ova/gram in liver tissue (with reduction percent of 63.07% and 78.26%, respectively). Schistosomal oogram patterns, immature and mature ova, also showed a significant decrease. The reduction in granuloma number and size was 40.63% and 48.66%, respectively, in GIII, whereas in GIV, the reduction percent was 76.63% and 67.08%. In addition, the degree of fibrosis was significantly diminished in both treated groups. GIV showed significant reduction in IL-1β and SMA expression and increase in SIRT3 expression. These findings reveal how auranofin suppresses the development of liver fibrosis. Therefore, it is crucial to take another look at auranofin as a prospective medication for the treatment of S. mansoni egg-induced hepatic granuloma and consequent fibrosis.

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“…[57,58] NLRP3 inflammasome activation in myeloid cells seems to be of special relevance for the progression of NAFLD to fibrotic NASH as observed in mice challenged by a western-type diet. [59] NLRP3 and related release of IL-1-type cytokines play a relevant role as mediators of hepatic fibrosis. [60,61] The NLRP3 inflammasome directly triggers upregulation of fibrotic markers at both mRNA and protein levels in activated HSCs, and importantly, Nlrp3 knock-in mice exhibited liver fibrosis with an increase in alpha-smooth muscle actin and collagen production independent of inflammatory infiltration.…”

Section: Inflammasomes In Liver Inflammationmentioning

confidence: 99%

“…Both NLRP3 inflammasome/IL-1β and also IL-1β are crucially involved in the pathogenesis of murine acetaminophen hepatotoxicity by activating IL-1RI 57,58 . NLRP3 inflammasome activation in myeloid cells seems to be of special relevance for the progression of NAFLD to fibrotic NASH as observed in mice challenged by a western-type diet 59 . NLRP3 and related release of IL-1-type cytokines play a relevant role as mediators of hepatic fibrosis 60,61 .…”

Section: Concepts Of Inflammation In Chronic Liver Diseasesmentioning

confidence: 99%

Therapeutic modulation of the liver immune microenvironment

2023

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Inflammation is a hallmark of progressive liver diseases such as chronic viral or immune-mediated hepatitis, alcohol-associated liver disease, and NAFLD. Preclinical and clinical studies have provided robust evidence that cytokines and related cellular stress sensors in innate and adaptive immunity orchestrate hepatic disease processes. Unresolved inflammation and liver injury result in hepatic scarring, fibrosis, and cirrhosis, which may culminate in HCC. Liver diseases are accompanied by gut dysbiosis and a bloom of pathobionts, fueling hepatic inflammation. Anti-inflammatory strategies are extensively used to treat human immune-mediated conditions beyond the liver, while evidence for immunomodulatory therapies and cell therapy–based strategies in liver diseases is only emerging. The development and establishment of novel immunomodulatory therapies for chronic liver diseases has been dampened by several clinical challenges, such as invasive monitoring of therapeutic efficacy with liver biopsy in clinical trials and risk of DILI in several studies. Such aspects prevented advancements of novel medical therapies for chronic inflammatory liver diseases. New concepts modulating the liver immune environment are studied and eagerly awaited to improve the management of chronic liver diseases in the future.

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Cell-specific Deletion of NLRP3 Inflammasome Identifies Myeloid Cells as Key Drivers of Liver Inflammation and Fibrosis in Murine Steatohepatitis

Cited by 27 publications

References 35 publications

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Auranofin attenuates Schistosoma mansoni egg-induced liver granuloma and fibrosis in mice

Therapeutic modulation of the liver immune microenvironment

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