Myeloid Nrf2 deficiency aggravates non-alcoholic steatohepatitis progression by regulating YAP-mediated NLRP3 inflammasome signaling

Wang, Peng; Ni, Ming; Tian, Yizhu; Wang, Hao; Qiu, Jiannan; You, Wenhua; Wei, Song; Shi, Yong; Zhou, Jiang; Cheng, Feng; Rao, Jianhua; Lü, Ling

doi:10.1016/j.isci.2021.102427

Cited by 24 publications

(18 citation statements)

References 46 publications

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“…In line with our results, the activation of NRF2 protected against hepatocyte steatosis in nutritionally induced nonalcoholic steatohepatitis in mice . Furthermore, myeloid NRF2 deficiency aggravated nonalcoholic steatohepatitis progression . However, some study also reported that hepatocyte-specific NRF2 deficiency mitigated high-fat-diet-induced hepatic steatosis .…”

Section: Discussionsupporting

confidence: 90%

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Genistein Protects against Acetaldehyde-Induced Oxidative Stress and Hepatocyte Injury in Chronic Alcohol-Fed Mice

Ding

Hao

et al. 2023

J. Agric. Food Chem.

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Alcohol-related liver disease (ALD) is one of the most prevalent forms of liver disease in the world. Acetaldehyde, an intermediate product of alcohol catabolism, is a cause of liver injury caused by alcohol. This study was designed to evaluate the protective role and mechanism(s) of genistein against acetaldehyde-induced liver injury in the pathological process of ALD. We found that genistein administration significantly ameliorated alcohol-induced hepatic steatosis, injury, and inflammation in mice. Genistein supplementation markedly reversed hepatic oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and hepatocellular apoptosis in both alcohol-fed mice liver and acetaldehyde-treated hepatocytes. The mechanistic experiments revealed that the restoration of genistein administration rescued heme oxygenase-1 (HO-1) reduction at both transcriptional and protein levels in either alcohol-fed mice liver or acetaldehyde-treated hepatocytes, and the beneficial aspects derived from genistein were abolished in antioxidase heme oxygenase-1 (HO-1)-deficient hepatocytes. Moreover, we confirmed that genistein administrationrestored hepatic nuclear factor erythroid 2-related factor 2 (NRF2), a key transcriptional regulator of HO-1, was involved in the protective role of genistein in ALD. This study demonstrated that genistein ameliorated acetaldehyde-induced oxidative stress and liver injury by restoring the hepatic NRF2−HO-1 signaling pathway in response to chronic alcohol consumption. Therefore, genistein may serve as a potential therapeutic choice for the treatment of ALD.

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Section: Discussionsupporting

confidence: 90%

“…63 Furthermore, myeloid NRF2 deficiency aggravated nonalcoholic steatohepatitis progression. 64 However, some study also reported that hepatocyte-specific NRF2 deficiency mitigated high-fat-diet-induced hepatic steatosis. 65 NRF2 also promoted the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.…”

Section: ■ Discussionmentioning

confidence: 99%

Genistein Protects against Acetaldehyde-Induced Oxidative Stress and Hepatocyte Injury in Chronic Alcohol-Fed Mice

Ding

Hao

et al. 2023

J. Agric. Food Chem.

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“…In NASH models, the NLRP3 inflammasome activation in KCs or BMDMs caused inflammatory cytokine production, contributing to lipid synthesis in hepatocytes and fibrotic collagen production in HSCs ( 71 – 73 ). Furthermore, macrophage-specific Nrf2 knockout aggravated NASH progression by initiating ROS and IL-1β in a yes-associated protein (YAP)–NLRP3-dependent manner ( 74 ). This finding demonstrates the role of ROS in activating the NLRP3 inflammasome in NASH.…”

Section: Inflammasome and Pyroptosis In Liver Fibrosismentioning

confidence: 99%

Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis

et al. 2022

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Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis via different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.

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“…Similarly, Nrf2 can increase NQO1 production and lead to negative effects on NLRP3 inflammasome activation (200). In addition, Hippo-yes-associated protein signaling can also be viewed as a mechanism of Nrf2 activation alleviating inflammation related to NLRP3 inflammasome activation (202).…”

Section: Nrf2 and Nf-kb Signalingmentioning

confidence: 99%

Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

Wang

2022

Front. Immunol.

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Macrophages are the most abundant immune cells within the synovial joints, and also the main innate immune effector cells triggering the initial inflammatory responses in the pathological process of osteoarthritis (OA). The transition of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes can play a key role in building the intra-articular microenvironment. The pro-inflammatory cascade induced by TNF-α, IL-1β, and IL-6 is closely related to M1 macrophages, resulting in the production of pro-chondrolytic mediators. However, IL-10, IL1RA, CCL-18, IGF, and TGF are closely related to M2 macrophages, leading to the protection of cartilage and the promoted regeneration. The inhibition of NF-κB signaling pathway is central in OA treatment via controlling inflammatory responses in macrophages, while the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears not to attract widespread attention in the field. Nrf2 is a transcription factor encoding a large number of antioxidant enzymes. The activation of Nrf2 can have antioxidant and anti-inflammatory effects, which can also have complex crosstalk with NF-κB signaling pathway. The activation of Nrf2 can inhibit the M1 polarization and promote the M2 polarization through potential signaling transductions including TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways, with the regulation or cooperation of Notch, NLRP3, PI3K/Akt, and MAPK signaling. And the expression of heme oxygenase-1 (HO-1) and the negative regulation of Nrf2 for NF-κB can be the main mechanisms for promotion. Furthermore, the candidates of OA treatment by activating Nrf2 to promote M2 phenotype macrophages in OA are also reviewed in this work, such as itaconate and fumarate derivatives, curcumin, quercetin, melatonin, mesenchymal stem cells, and low-intensity pulsed ultrasound.

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Myeloid Nrf2 deficiency aggravates non-alcoholic steatohepatitis progression by regulating YAP-mediated NLRP3 inflammasome signaling

Abstract: Highlights Kupffer cells Nrf2 was downregulated in both human and mouse NASH livers Myeloid Nrf2 deficiency aggravates liver steatosis and inflammation in HFDinduced NASH Nrf2 controls the NLRP3 activation in a ROSmediated Hippo-YAP signaling manner

Cited by 24 publications

References 46 publications

Genistein Protects against Acetaldehyde-Induced Oxidative Stress and Hepatocyte Injury in Chronic Alcohol-Fed Mice

Genistein Protects against Acetaldehyde-Induced Oxidative Stress and Hepatocyte Injury in Chronic Alcohol-Fed Mice

Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis

Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

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