Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury

Frissen, Mick; Liao, Lijun; Schneider, Kai Markus; Djudjaj, Sonja; Haybaeck, Johannes; Wree, Alexander; Rolle-Kampczyk, Ulrike; Bergen, Martin von; Latz, Eicke; Boor, Peter; Trautwein, Christian

doi:10.1002/hep.31494

Cited by 63 publications

(65 citation statements)

References 55 publications

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“…BDL leads to the stasis of bile acids in the liver. Excess accumulation of toxic bile salts in hepatocytes results in inflammatory reactions, hepatocyte necrosis, and peri-ductular fibrosis (Frissen et al, 2020). HSC activation plays a pivotal role in the development of liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 Omega-Hydroxylase 4a14 Attenuates Cholestatic Liver Fibrosis

Wang

Zhang

et al. 2021

Front. Physiol.

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BackgroundCholestasis is a pathological condition involving obstruction of bile secretion and excretion that results in hepatotoxicity, inflammation, fibrosis, cirrhosis, and eventually liver failure. Common bile duct ligation (BDL) model is a well-established murine model to mimic cholestatic liver fibrosis. We previously reported that cytochrome P450 omega-hydroxylase 4a14 (Cyp4a14) plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD)-related fibrosis. The goal of this study was to determine the role of Cyp4a14 in cholestatic-induced liver fibrosis.MethodsC57BL/6 mice were subjected to BDL for 14 days, and Cyp4a14 mRNA and protein levels were examined and compared with those of the sham group. Cyp4a14 knockout mice and adeno-associated virus (AAV)-mediated overexpression of Cyp4a14 in C57BL/6 mice underwent BDL and liver histology, and key fibrosis markers were examined.ResultsBoth hepatic Cyp4a14 mRNA and protein levels were markedly reduced in BDL liver compared with the time-matched sham group. Cyp4a14 gene-deficient mice aggravates whereas its overexpression alleviates BDL-induced hepatic fibrosis, which were determined by liver function, liver histology, and levels of key fibrotic markers including α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and collagen 1a2 (Col1a2).ConclusionCyp4a14 exerts a contrasting role in different hepatic fibrosis models. Strategies that enhance Cyp4a14 activity may be potential strategies to cholestatic related liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450 Omega-Hydroxylase 4a14 Attenuates Cholestatic Liver Fibrosis

Wang

Zhang

et al. 2021

Front. Physiol.

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“…MCC950 is one of the most potent and selective NLRP3 inhibitors discovered to date and it can bind directly and specifically to NLRP3, irrespective of its activation state (10). More recently, MCC950 was reported to alleviate chronic cholestatic liver injury (11), fulminant hepatitis (12), and liver fibrosis (13). However, little is known about the role of MCC950 treatment in CCl 4 -induced acute liver injury.…”

Section: Introductionmentioning

confidence: 99%

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

et al. 2021

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Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.

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“…In the present study, we found that BDL signi cantly increased serum levels of TNFα, IL-1β, and IL-6 in mice, which may directly damage cholangiocytes and reduce the expression of bile transporters in cholangiocytes, increasing the accumulation of bile acids in the liver and deteriorating liver injury and brosis [40]. Actually, a reduction in pro-in ammatory cytokine production and inhibiting the in ammatory pathway can drastically mitigate the liver injury, retarding the process of cirrhosis in BDL rodents [41]. We found that activation of a7nAChR signi cantly decreased serum levels of TNFα, IL-1β and IL-6 in BDL mice, which were associated with liver injury in BDL mice.…”

Section: Discussionmentioning

confidence: 79%

Activation of α7nAChR Preserves Intestinal Barrier Integrity and Ameliorates Cholestasis Liver Fibrosis in Mice by Enhancing the HO-1 / STAT3 Signaling to Inhibit NF-κB Activation

Lei

Zhao

Sun

et al. 2021

Preprint

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Background: Activation of alpha-7 nicotinic acetylcholine receptor (α7nAChR) can inhibit the systemic inflammatory response and preserve intestinal barrier integrity. This study aimed at elucidating the molecular mechanisms by which α7nAChR activation could inhibit intestinal barrier injury and cholestatic liver fibrosis in mice induced by bile duct ligation (BDL).Methods: The intestine-specific HO-1 knockout VillinCreHmox1-/- and control Hmox1floxp/floxp C57BL/6 mice were subjected to BDL. The therapeutic effects of GST-21, a specific ligand for α7nAChR, on systemic and intestinal inflammation, intestinal barrier integrity, liver fibrosis and injury, HO-1 expression, STAT3, AKT and NF-kBp65 activation were examined in these mice and intestinal epithelial cells co-cultured with macrophages. Results: Compared with BDL mice, α7nAChR activation by GST-21 decreased intestinal and liver injury and fibrosis in BDL mice, accompanied by reducing serum cytokine responses. In addition, activation of α7nAChR preserved the tight junction protein expression and intestinal epithelial cell barrier integrity in BDL mice and epithelial cells co-cultured with macrophages. The therapeutic effects of α7nAChR activation were mediated by enhancing HO-1 expression, STAT3 phosphorylation, and reducing the NF-kBp65 activation in intestinal tissues and epithelial cells co-cultured with macrophages. Finally, activation of α7nAChR induced HO-1 expression and STAT3 phosphorylation in an interdependent manner, independent of the PI3K/AKT signaling. Conclusion: Activation of α7nAChR enhanced HO-1 expression and STAT3 signaling to inhibit NF-κB activation, preserving the intestinal barrier integrity, and reducing inflammation and liver fibrosis in cholestasis mice. Therefore, targeting α7nAChR may be a promising interventional strategy for primary biliary cholangitis.

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Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury

Cited by 63 publications

References 55 publications

Cytochrome P450 Omega-Hydroxylase 4a14 Attenuates Cholestatic Liver Fibrosis

Cytochrome P450 Omega-Hydroxylase 4a14 Attenuates Cholestatic Liver Fibrosis

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

Activation of α7nAChR Preserves Intestinal Barrier Integrity and Ameliorates Cholestasis Liver Fibrosis in Mice by Enhancing the HO-1 / STAT3 Signaling to Inhibit NF-κB Activation

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