RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1–TLR4–NF‐κB pathway in macrophages

Wei, Song; Zhou, Haoming; Wang, Qi; Zhou, Shun; Li, Changyong; Li, Rui; Qiu, Jiannan; Shi, Chengyu; Lü, Ling

doi:10.1096/fj.201900752r

Cited by 35 publications

(31 citation statements)

References 33 publications

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“…RIP3-dependent necrosis is widely believed to contribute to several detrimental pathologies. Conversely, RIP3 is profoundly important for inflammation, in part through regulating NF-κB activity 47 . Here, we found that TSZ-induced expression of CCR5 was severely inhibited in RIP3−/− BMDMs, and the NF-κB inhibitor PDTC blocked TSZ-induced CCR5 expression.…”

Section: Discussionmentioning

confidence: 99%

CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest

et al. 2021

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The pathogenesis of bronchopulmonary dysplasia (BPD), involves inflammatory, mechanisms that are not fully characterized. Here we report that overexpression of C-C chemokine receptor 5 (CCR5) and its ligands is associated with BPD development. Lipopolysaccharide-induced BPD rats have increased CCR5 and interleukin-1β (IL-1β) levels, and decreased alveolarization, while CCR5 or IL-1β receptor antagonist treatments decreased inflammation and increased alveolarization. CCR5 enhances macrophage migration, macrophage infiltration in the lungs, IL-1β levels, lysyl oxidase activity, and alveolar development arrest. CCR5 expression on monocytes, and its ligands in blood samples from BPD infants, are elevated. Furthermore, batyl alcohol supplementation reduced CCR5 expression and IL-1β production in lipopolysaccharide-exposed rat lungs. Moreover, receptor-interacting kinase 3 (RIP3) upstream regulator of CCR5-cultured RIP3−/− macrophages exhibited partly blocked lipopolysaccharide-induced CCR5 expression. We conclude that increased CCR5 expression is a key mechanism in BPD development and represents a novel therapeutic target for treatment.

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Section: Discussionmentioning

confidence: 99%

CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest

et al. 2021

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“…Sprague‐Dawley rats (Forty) were obtained from the Anhui Medical University, Experimental Animal Center. SD rats were intraperitoneally injected twice‐weekly for 12 weeks with a mixture of carbon tetrachloride (CCl 4 )/olive oil in a 1:1 (vol/vol) ratio at 1 mL/kg . All animal experiments were approved by the Institutional Animal Care and Use Committee of Anhui Medical University.…”

Section: Methodsmentioning

confidence: 99%

“…SD rats were intraperitoneally injected twice-weekly for 12 weeks with a mixture of carbon tetrachloride (CCl 4 )/olive oil in a 1:1 (vol/vol) ratio at 1 mL/kg. 16 All animal experiments were approved by the Institutional Animal Care and Use Committee of Anhui Medical University. Twelve weeks later, the animals were anaesthetized, the rats were then sacrificed and liver tissues collected.…”

Section: Animal Models Of Liver Fibrosismentioning

confidence: 99%

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

Yang

Zhang

et al. 2020

J Cellular Molecular Medi

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Long non‐coding RNAs (LncRNAs) and DNA methylation are important epigenetic mark play a key role in liver fibrosis. Currently, how DNA methylation and LncRNAs control the hepatic stellate cell (HSC) activation and fibrosis has not yet been fully characterized. Here, we explored the role of antisense non‐coding RNA in the INK4 locus (ANRIL) and DNA methylation in HSC activation and fibrosis. The expression levels of DNA methyltransferases 3A (DNMT3A), ANRIL, α‐Smooth muscle actin (α‐SMA), Type I collagen (Col1A1), adenosine monophosphate‐activated protein kinase (AMPK) and p‐AMPK in rat and human liver fibrosis were detected by immunohistochemistry, qRT‐PCR and Western blotting. Liver tissue histomorphology was examined by haematoxylin and eosin (H&E), Sirius red and Masson staining. HSC was transfected with DNMT3A‐siRNA, over‐expressing ANRIL and down‐regulating ANRIL. Moreover, cell proliferation ability was examined by CCK‐8, MTT and cell cycle assay. Here, our study demonstrated that ANRIL was significantly decreased in activated HSC and liver fibrosis tissues, while Col1A1, α‐SMA and DNMT3A were significantly increased in activated HSC and liver fibrosis tissues. Further, we found that down‐regulating DNMT3A expression leads to inhibition of HSC activation. Reduction in DNMT3A elevated ANRIL expression in activated HSC. Furthermore, we performed the over expression ANRIL suppresses HSC activation and AMPK signalling pathways. In sum, our study found that epigenetic DNMT3A silencing of ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway. Targeting epigenetic modulators DNMT3A and ANRIL, and offer a novel approach for liver fibrosis therapy.

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“…It was previously reported that the RhoA/ROCK pathway governed TLR4/NF-kB signaling and accelerated inflammation [32]. Previous studies have shown that ROCK1 was the upstream mediator of TLR4 in macrophages during liver fibrosis [33]. With the use of the ROCK inhibitor, Y-27632, Hutchinson et al showed that the inflammatory cascade activated TLR4 signaling through ROCK [34].…”

Section: Control Hfdmentioning

confidence: 99%

The Effects of RKI-1447 in a Mouse Model of Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet and in HepG2 Human Hepatocellular Carcinoma Cells Treated with Oleic Acid

Wang

Jiang²

2020

Med Sci Monit

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Background: This study aimed to investigate the effects of RKI-1447, a selective inhibitor of Rho-associated ROCK kinases, in a mouse model of nonalcoholic fatty liver disease (NAFLD) induced by a high-fat diet, and in oleic acid-treated HepG2 human hepatocellular carcinoma cells in vitro. Material/Methods: Four study groups of mice included: the control group; the high-fat diet (HFD) group; the HFD+RKI-1447 (2 mg/kg) group; and the HFD+RKI-1447 (8 mg/kg) group. Mice were fed a high-fat diet for 12 weeks. Mice in the HFD+RKI-1447 groups were fed a high-fat diet for 12 weeks and treated with RKI-1447 twice weekly for three weeks. The HepG2 human hepatocellular carcinoma cells were treated with or without RKI-1447 for 2 h and treated with oleic acid for 24 h. Results: In the mouse model of NAFLD, RKI-1447 reduced insulin resistance and the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), total cholesterol, triglyceride, interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), malondialdehyde (MDA), and superoxide dismutase (SOD). RKI-1447 reduced the histological changes in the mouse model of NAFLD in mice fed a high-fat diet and significantly inhibited the generations of triglyceride, IL-6, and TNF-a. RKI-1447 reduced the levels of oxidative stress in HepG2 cells treated with oleic acid and significantly down-regulated the expression of RhoA, ROCK1, ROCK2, toll-like receptor 4 (TLR4), p-TBK1, and p-IRF3. RKI-1447 treatment also inhibited RhoA expression. Conclusions: In a mouse model of NAFLD, RKI-1447 inhibited ROCK and modulated insulin resistance, oxidative stress, and inflammation through the ROCK/TLR4/TBK1/IRF3 pathway.

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RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1–TLR4–NF‐κB pathway in macrophages

Cited by 35 publications

References 33 publications

CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest

CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

The Effects of RKI-1447 in a Mouse Model of Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet and in HepG2 Human Hepatocellular Carcinoma Cells Treated with Oleic Acid

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