c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis

Leslie, Jack; Macia, Marina García; Luli, Saimir; Worrell, Julie C.; Reilly, William J.; Paish, Hannah L; Knox, Amber; Barksby, Ben S.; Gee, Lucy; Zaki, Marco Y.W.; Collins, Amy; Burgoyne, Rachel A.; Cameron, Rainie; Bragg, Charlotte; Chung, Git; Brown, Charles D.; Blanchard, Andy; Nanthakumar, Carmel B.; Karsdal, Morten A.; Robinson, Stuart; Manas, Derek; Sen, Gourab; French, Jeremy; White, Steven A.; Murphy, Sandra; Trost, Matthias; Zakrzewski, Johannes L.; Klein, Ulf; Schwabe, Robert F.; Mederacke, Ingmar; Nixon, Colin; Bird, Tom; Teuwen, Laure-Anne; Schoonjans, Luc; Carmeliet, Peter; Mann, Jelena; Fisher, Andrew J.; Sheerin, Neil; Borthwick, Lee A.; Mann, Derek A.; Oakley, Fiona

doi:10.1038/s42255-020-00306-2

Cited by 24 publications

(22 citation statements)

References 94 publications

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“…It is implicated that c‐Rel, a member of the NF‐κB family, plays a critical role in hepatocyte‐macrophage crosstalk. C‐Rel signaling in macrophages promotes the hepatocytes to pro‐inflammatory phenotype, which in turn exacerbates macrophages into fibrogenic phenotype, and subsequently induces the activation of myofibroblasts in CCl4‐induced liver fibrosis 78 …”

Section: Hepatic Macrophages In the Progression Of Liver Fibrosismentioning

confidence: 99%

“…Notably, c‐Rel is a key player in orchestrating metabolic reprogramming in macrophages, which facilitates the macrophage polarisation. C‐Rel signaling promotes mitochondrial respiration and subsequently induces M2 polarisation via binding to the promoter of 6‐phosphofructo‐2‐kinase (PFKFB1), eventually inducing HSCs activation in CCI4‐induced injury 78 . Dysregulation of iron metabolism and hepatic iron overload are associated with NASH and advanced liver fibrosis 82 .…”

Section: Hepatic Macrophages In the Progression Of Liver Fibrosismentioning

confidence: 99%

“…C-Rel signaling in macrophages promotes the hepatocytes to proinflammatory phenotype, which in turn exacerbates macrophages into fibrogenic phenotype, and subsequently induces the activation of myofibroblasts in CCl4-induced liver fibrosis. 78…”

Section: Interactions With Hepatocytesmentioning

confidence: 99%

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Hepatic macrophages: Key players in the development and progression of liver fibrosis

Cheng

Chai

Wang

et al. 2021

Liver International

113

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Hepatic fibrosis is a common pathological process involving persistent liver injury with various etiologies and subsequent inflammatory responses that occur in chronic liver diseases. If left untreated, liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma and eventually, liver failure. Unfortunately, to date, there is no effective treatment for liver fibrosis, with the exception of liver transplantation. Although the pathophysiology of liver fibrosis is multifactorial and includes the activation of hepatic stellate cells, which are known to drive liver fibrogenesis, hepatic macrophages have emerged as central players in the development of liver fibrosis and regression. Hepatic macrophages, which consist of resident macrophages (Kupffer cells) and monocyte‐derived macrophages, have been shown to play an intricate role in the initiation of inflammatory responses to liver injury, progression of fibrosis, and promotion of fibrosis resolution. These features have made hepatic macrophages uniquely attractive therapeutic targets in the fight against hepatic fibrosis. In this review, we synthesised the literature to highlight the functions and regulation of heterogeneity in hepatic macrophages. Furthermore, using the existing findings, we attempt to offer insights into the molecular mechanisms underlying the phenotypic switch from fibrogenic macrophages to restorative macrophages, the regulation of heterogeneity, and modes of action for hepatic macrophages. A better understanding of these mechanisms may guide the development of novel anti‐fibrotic therapies (eg macrophage subset‐targeted treatments) to combat liver fibrosis in the future.

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Section: Hepatic Macrophages In the Progression Of Liver Fibrosismentioning

confidence: 99%

Section: Hepatic Macrophages In the Progression Of Liver Fibrosismentioning

confidence: 99%

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Hepatic macrophages: Key players in the development and progression of liver fibrosis

Cheng

Chai

Wang

et al. 2021

Liver International

113

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“…Tissue sections were subjected to heat-induced antigen retrieval in EDTA, pH 8.0 for CD3 and sodium citrate buffer, pH 6.0 for CD68. Non-specific protein binding was blocked using 20% swine serum at room temperature for 30 minutes, and then antibodies specific to CD3 (dilution 1:100; MCA1477, Bio-Rad), and CD68 (dilution 1:200; OABB00472, Aviva Systems Biology) were incubated overnight at 4°C (Leslie et al, 2020). The following day slides were washed with PBS and then incubated with the appropriate biotinylated secondary antibody; swine anti-rabbit 1:200 (eo353 Dako) for CD68 or goat anti-rat 1:200 (STAR80B Serotec) for CD3.…”

Section: Methodsmentioning

confidence: 99%

The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection

Bilkei‐Gorzo

Heunis

Fabrikova

et al. 2021

Preprint

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Phagocytosis as a key process in innate immunity and homeostasis. After uptake, newly formed phagosomes mature by acquisition of endo-lysosomal enzymes. Macrophage activation by interferon-gamma (IFN-γ) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN-γ activation of macrophages, suggesting a role in regulating phagosomal functions. Furthermore, we identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-γ activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to Staphylococcus aureus, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock-out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections.

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“…Recently, the critical role of c-Rel (the subunit of NF-κ-B) in regulating metabolic changes required for inflammatory and fibrogenic activities of macrophages and hepatocytes was reported by Leslie et al (2020) . In CCl 4 -induced liver fibrosis, independent knockout of Rel in macrophages or hepatocytes inhibited liver fibrosis, while combined knockout in both cell types had an additive antifibrosis effect.…”

Section: Cell Targets In Liver Fibrosismentioning

confidence: 99%

Nanotechnology in Drug Delivery for Liver Fibrosis

Zhang

et al. 2022

Front. Mol. Biosci.

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Liver fibrosis is a reversible disease course caused by various liver injury etiologies, and it can lead to severe complications, such as liver cirrhosis, liver failure, and even liver cancer. Traditional pharmacotherapy has several limitations, such as inadequate therapeutic effect and side effects. Nanotechnology in drug delivery for liver fibrosis has exhibited great potential. Nanomedicine improves the internalization and penetration, which facilitates targeted drug delivery, combination therapy, and theranostics. Here, we focus on new targets and new mechanisms in liver fibrosis, as well as recent designs and development work of nanotechnology in delivery systems for liver fibrosis treatment.

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c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis

Abstract: This is a repository copy of c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.

Cited by 24 publications

References 94 publications

Hepatic macrophages: Key players in the development and progression of liver fibrosis

Hepatic macrophages: Key players in the development and progression of liver fibrosis

The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection

Nanotechnology in Drug Delivery for Liver Fibrosis

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