Capillin protects against non-alcoholic steatohepatitis through suppressing NLRP3 inflammasome activation and oxidative stress

Li, Bin; Wang, Rui; Wang, Lei; Zhang, Gucheng; Zhang, Yang

doi:10.1080/08923973.2021.1984520

Cited by 13 publications

(10 citation statements)

References 45 publications

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“…S1). To better understand the placement of VDAC oligomerization in the sequence of events leading to NLRP3 inflammasome activation, we asked whether LPS priming of BMDMs was necessary for VDAC oligomerization because priming is known to prepare BMDMs by promoting expression of NLRP3 and its association with the mitochondrial outer membrane through association with cardiolipin ( 23 – 25 ). We observed that HK-TAT induced VDAC1 oligomerization in unprimed BMDMs (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Compelling evidence implicates a role for mitochondria in regulation of the NLRP3 inflammasome. Mitochondrial dysfunction (18), reactive oxygen, release of mitochondrial DNA (mtDNA) (19)(20)(21)(22), exposure of cardiolipin on mitochondrial outer membranes (23)(24)(25), and viral activation of NLRP3 via sensing by mitochondrial antiviral signaling protein (MAVS) (26,27) have all been linked to NLRP3 inflammasome activation. Further, mitochondria have been proposed as a site of initial inflammasome nucleation (28).…”

Section: Introductionmentioning

confidence: 99%

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Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation

Baik,

Ramanujan,

Becker

et al. 2023

Sci. Immunol.

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NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer’s disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation

Baik,

Ramanujan,

Becker

et al. 2023

Sci. Immunol.

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“…Upregulation and activation of the NLRP3 inflammasome by cardiolipin is crucial in NASH pathogenesis. Moreover, the inhibition of cardiolipin can suppress NLRP3 inflammasome activation, thereby improving and ameliorating symptoms of NASH ( Liu et al, 2019 ).…”

Section: Activation Of the Nlrp3 Inflammasome In Non-alcoholic Fatty ...mentioning

confidence: 99%

The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment

Wang

et al. 2022

Front. Pharmacol.

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Non-alcoholic fatty liver disease (NAFLD) is among the most prevalent primary liver diseases worldwide and can develop into various conditions, ranging from simple steatosis, through non-alcoholic steatohepatitis (NASH), to fibrosis, and eventually cirrhosis and hepatocellular carcinoma. Nevertheless, there is no effective treatment for NAFLD due to the complicated etiology. Recently, activation of the NLPR3 inflammasome has been demonstrated to be a contributing factor in the development of NAFLD, particularly as a modulator of progression from initial hepatic steatosis to NASH. NLRP3 inflammasome, as a caspase-1 activation platform, is critical for processing key pro-inflammatory cytokines and pyroptosis. Various stimuli involved in NAFLD can activate the NLRP3 inflammasome, depending on the diverse cellular stresses that they cause. NLRP3 inflammasome-related inhibitors and agents for NAFLD treatment have been tested and demonstrated positive effects in experimental models. Meanwhile, some drugs have been applied in clinical studies, supporting this therapeutic approach. In this review, we discuss the activation, biological functions, and treatment targeting the NLRP3 inflammasome in the context of NAFLD progression. Specifically, we focus on the different types of therapeutic agents that can inhibit the NLRP3 inflammasome and summarize their pharmacological effectiveness for NAFLD treatment.

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“…Cardiolipin oxidation and hydrolysis are a key mechanism of ischemia-reperfusion-induced brain injury ( 100 ). Nowadays, cardiolipin is reported to be effective for triggering the activation of NLRP3 inflammasome ( 101 ) after acute ischemia ( 102 ). On one hand, cardiolipin directly interacts with both the N-terminal leucine-rich repeat (LRR) of NLRP3 and full-length of caspase-1 of NLRP3 inflammasome ( 86 , 103 ).…”

Section: Mitochondria Regulate Nlrp3 Inflammasome Activation During I...mentioning

confidence: 99%

Focus on the role of mitochondria in NLRP3 inflammasome activation: A prospective target for the treatment of ischemic stroke (Review)

et al. 2022

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Post-ischemic neuroinflammation induced by the innate local immune response is a major pathophysiological feature of cerebral ischemic stroke, which remains the leading cause of mortality and disability worldwide. NLR family pyrin domain containing (NLRP)3 inflammasome crucially mediates post-ischemic inflammatory responses via its priming, activation and interleukin-1β release during hypoxic-ischemic brain damage. Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. In the present review, focus was addressed on the role of mitochondria in cerebral ischemic stroke while keeping NLRP3 inflammasome as a link. Under ischemia and hypoxia, mitochondria are capable of controlling NLRP3 inflammasome-mediated neuroinflammation through mitochondrial released contents, mitochondrial localization and mitochondrial related proteins. Thus, inflammasome and mitochondria may be attractive targets to treat ischemic stroke as well as the several drugs that target the process of mitochondrial function to treat cerebral ischemic stroke. At present, certain drugs have already been studied in clinical trials.

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Capillin protects against non-alcoholic steatohepatitis through suppressing NLRP3 inflammasome activation and oxidative stress

Cited by 13 publications

References 45 publications

Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation

Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation

The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment

Focus on the role of mitochondria in NLRP3 inflammasome activation: A prospective target for the treatment of ischemic stroke (Review)

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