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Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells.

ABSTRACT: The role of Foxo3a in the regulation of autophagy flux and activation of the NLRP3 inflammasome in KCs suffering from HFD conditions is unknown.Up-regulation of Foxo3a restored autophagy flux and dampened the activation of the NLRP3 inflammasome in KCs stimulated with PA and LPS. In contrast, down-regulation of Foxo3a increased blockage of autophagy flux and promoted NLRP3 inflammasome activation. Additionally, mRNA levels of Bim were significantly changed with the alteration of Foxo3a in KCs under PA and LPS stimulation among foxo3a targeted genes. Overexpression of Bim restored autophagy influx and attenuated NLRP3 inflammasome pathway activation. In addition, autophagy formation was restored, and activation of NLRP3 inflammasome was inhibited in KCs isolated from mice treated with Iturin A and fed with a HFD.Autophagy flux in KCs and activation levels of NLRP3 inflammasome were evaluated after altering the expression of Foxo3a in KCs before stimulation with PA and LPS. Additionally, various target genes of Foxo3a were measured in KCs pretreated with an agonist (Iturin A) or inhibitor (SC97) of Foxo3a after KCs stimulation with PA and LPS in order to hunt for targets of Foxo3a. Activation levels of NLRP3 inflammasome in isolated KCs, as well as autophagy flux, were measured after mice were treated with Iturin A and fed with a HFD for 16 weeks.Foxo3a restores autophagy flux and attenuates the activation of the NLRP3 inflammasome by promoting the transcription of Bim, suggesting a potential therapeutic target in NAFLD and other obesity-related diseases.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5470965 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells.

Liu Yan Y Zhang Wenfeng W Wu Xiaoling X Gong Jianping J

Oncotarget 20170501 21

<h4>Background</h4>The role of Foxo3a in the regulation of autophagy flux and activation of the NLRP3 inflammasome in KCs suffering from HFD conditions is unknown.<h4>Results</h4>Up-regulation of Foxo3a restored autophagy flux and dampened the activation of the NLRP3 inflammasome in KCs stimulated with PA and LPS. In contrast, down-regulation of Foxo3a increased blockage of autophagy flux and promoted NLRP3 inflammasome activation. Additionally, mRNA levels of Bim were significantly changed with ...[more]

PMID: 28427239

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Project description:Hepatic ischemia/reperfusion (I/R) contributes to major complications in clinical practice affecting perioperative morbidity and mortality. Recent evidence suggests the key role of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammaosme activation on the pathogenesis of I/R injury. Asiatic acid (AA) is a pentacyclic triterpene derivative presented with versatile activities, including antioxidant, anti-inflammation and hepatoprotective effects. This study was designed to determine whether AA had potential hepatoprotective benefits against hepatic I/R injury, as well as to unveil the underlying mechanisms involved in the putative effects. Mice subjected to warm hepatic I/R, and Kupffer cells (KCs) or RAW264.7 cells challenged with lipopolysaccharide (LPS)/H2O2, were pretreated with AA. Administration of AA significantly attenuated hepatic histopathological damage, global inflammatory level, apoptotic signaling level, as well as NLRP3 inflammasome activation. These effects were correlated with increased expression of peroxisome proliferator-activated receptor gamma (PPAR?). Conversely, pharmacological inhibition of PPAR? by GW9662 abolished the protective effects of AA on hepatic I/R injury and in turn aggravated NLRP3 inflammasome activation. Activation of NLRP3 inflammasome was most significant in nonparenchymal cells (NPCs). Depletion of KCs by gadolinium chloride (GdCl3) further attenuated the detrimental effects of GW9662 on hepatic I/R as well as NLRP3 activation. In vitro, AA concentration-dependently inhibited LPS/H2O2-induced NLRP3 inflammaosome activation in KCs and RAW264.7 cells. Either GW9662 or genetic knockdown of PPAR? abolished the AA-mediated inactivation of NLRP3 inflammasome. Mechanistically, AA attenuated I/R or LPS/H2O2-induced ROS production and phosphorylation level of JNK, p38 MAPK and I?B? but not ERK, a mechanism dependent on PPAR?. Finally, AA blocked the deleterious effects of LPS/H2O2-induced macrophage activation on hepatocyte viability in vitro, and improved survival in a lethal hepatic I/R injury model in vivo. Collectively, these data suggest that AA is effective in mitigating hepatic I/R injury through attenuation of KCs activation via PPAR?/NLRP3 inflammasome signaling pathway.

Project description:BACKGROUND:Previous studies reported that URB597 (URB) had therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuroinflammation and autophagy dysfunction. However, the interaction mechanisms underlying the CCH-induced abnormal excessive autophagy and neuroinflammation remain unknown. In this study, we investigated the roles of impaired autophagy in nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 3 inflammasome activation in the rat hippocampus and the underlying mechanisms under the condition of induced CCH as well as the effect of URB treatment. METHODS:The CCH rat model was established by bilateral common carotid artery occlusion (BCCAo), and rats were randomly divided into 11 groups as follows: (1) sham-operated, (2) BCCAo; (3) BCCAo+autophagy inhibitor 3-methyladenine (3-MA), (4) BCCAo+lysosome inhibitor chloroquine (CQ), (5) BCCAo+microglial activation inhibitor minocycline, (6) BCCAo+ROS scavenger N-acetylcysteine (NAC), (7) BCCAo+URB, (8) BCCAo+URB+3-MA, (9) BCCAo+URB+CQ, (10) BCCAo+URB+minocycline, (11) BCCAo+URB+NAC. The cell localizations of LC3, p62, LAMP1, TOM20 and NLRP3 were assessed by immunofluorescence staining. The levels of autophagy-related proteins (LC3, p62, LAMP1, BNIP3 and parkin), NLRP3 inflammasome-related proteins (NLRP3, CASP1 and IL-1?), microglial marker (OX-42) and proinflammatory cytokines (iNOS and COX-2) were evaluated by western blotting, and proinflammatory cytokines (IL-1? and TNF-a) were determined by ELISA. Reactive oxygen species (ROS) were assessed by dihydroethidium staining. The mitochondrial ultrastructural changes were examined by electron microscopy. RESULTS:CCH induced microglial overactivation and ROS accumulation, promoting the activation of the NLRP3 inflammasome and the release of IL-1?. Blocked autophagy and mitophagy flux enhanced the activation of the NLRP3-CASP1 inflammasome pathway. However, URB alleviated impaired autophagy and mitophagy by decreasing mitochondrial ROS and microglial overactivation as well as restoring lysosomal function, which would further inhibit the activation of the NLRP3-CASP1 inflammasome pathway. CONCLUSION:These findings extended previous studies indicating the function of URB in the mitigation of chronic ischemic injury of the brain.

Dataset Information

Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells.

Publications

Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells.

Similar Datasets

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