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Nuclear factor erythroid 2-related factor 2 regulates toll-like receptor 4 innate responses in mouse liver ischemia-reperfusion injury through Akt-forkhead box protein O1 signaling network.

ABSTRACT: Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant host defense, maintains the cellular redox homeostasis.This study was designed to investigate the role and molecular mechanisms by which Nrf2 regulates toll-like receptor (TLR)4-driven inflammation response in a mouse model of hepatic warm ischemia (90 min) and reperfusion (6 hr) injury (IRI).Activation of Nrf2 after preconditioning of wild-type mouse recipients with cobalt protoporphyrin ameliorated liver IRI, evidenced by improved hepatocellular function (serum alanine aminotransferase levels), and preserved tissue architecture (histology Suzuki's score). In marked contrast, ablation of Nrf2 signaling exacerbated IR-induced liver inflammation and damage in Nrf2 knockout hosts irrespective of adjunctive cobalt protoporphyrin treatment. The Nrf2 activation reduced macrophage and neutrophil trafficking, proinflammatory cytokine programs, and hepatocellular necrosis or apoptosis while increasing antiapoptotic functions in IR-stressed livers. At the molecular level, Nrf2 activation augmented heme oxygenase-1 expression and Stat3 phosphorylation and promoted PI3K-Akt while suppressing forkhead box O (Foxo)1 signaling. In contrast, Nrf2 deficiency diminished PI3K-Akt and enhanced Foxo1 expression in the ischemic livers. In parallel in vitro studies, Nrf2 knockdown in lipopolysaccharide-stimulated bone marrow-stimulated bone marrow-derived macrophages (BMMs) decreased heme oxygenase-1 and PI3K-Akt yet increased Foxo1 transcription, leading to enhanced expression of TLR4 proinflammatory mediators. Moreover, pretreatment of bone marrow-derived macrophages with PI3K inhibitor (LY294002) activated Foxo1 signaling, which in turn enhanced TLR4-driven innate responses in vitro.Activation of Nrf2 promoted PI3K-Akt, and inhibited Foxo1 activity in IR-triggered local inflammation response. By identifying a novel integrated Nrf2-Akt-Foxo1 signaling network in PI3K-dependent regulation of TLR4-driven innate immune activation, this study provides the rationale for refined therapeutic approaches to manage liver inflammation and IRI in transplant recipients.

SUBMITTER: Huang J

PROVIDER: S-EPMC4188703 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Nuclear factor erythroid 2-related factor 2 regulates toll-like receptor 4 innate responses in mouse liver ischemia-reperfusion injury through Akt-forkhead box protein O1 signaling network.

Huang Jing J Yue Shi S Ke Bibo B Zhu Jianjun J Shen Xiu-da XD Zhai Yuan Y Yamamoto Masayuki M Busuttil Ronald W RW Kupiec-Weglinski Jerzy W JW

Transplantation 20141001 7

<h4>Background</h4>Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant host defense, maintains the cellular redox homeostasis.<h4>Methods</h4>This study was designed to investigate the role and molecular mechanisms by which Nrf2 regulates toll-like receptor (TLR)4-driven inflammation response in a mouse model of hepatic warm ischemia (90 min) and reperfusion (6 hr) injury (IRI).<h4>Results</h4>Activation of Nrf2 after preconditioning of wild-type mouse recip ...[more]

PMID: 25171655

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Project description:Background and aimsHepatic macrophages can be activated by many factors such as gut-derived bacterial components and factors released from damaged hepatocytes. Macrophage polarization toward a proinflammatory phenotype (M1) represents an important event in the disease progression of nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms remain incompletely understood. Exosomes have been identified as important mediators for cell-cell communication by transferring various biological components such as microRNAs (miRs), proteins, and lipids. The role of exosomes in crosstalk between hepatocytes and macrophages in disease progression of NAFLD is yet to be explored.Approach and resultsIn the present study, we reported that lipotoxic injury-induced release of hepatocyte exosomes enriched with miR-192-5p played a critical role in the activation of M1 macrophages and hepatic inflammation. Serum miR-192-5p levels in patients with NAFLD positively correlated with hepatic inflammatory activity score and disease progression. Similarly, the serum miR-192-5p level and the number of M1 macrophages, as well as the expression levels of the hepatic proinflammatory mediators, were correlated with disease progression in high-fat high-cholesterol diet-fed rat models. Lipotoxic hepatocytes released more miR-192-5p-enriched exosomes than controls, which induced M1 macrophage (cluster of differentiation 11b-positive [CD11b+ ]/CD86+ ) activation and increase of inducible nitric oxide synthase, interleukin 6, and tumor necrosis factor alpha expression. Furthermore, hepatocyte-derived exosomal miR-192-5p inhibited the protein expression of the rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), which further inhibited the phosphorylation levels of Akt and forkhead box transcription factor O1 (FoxO1) and resulted in activation of FoxO1 and subsequent induction of the inflammatory response.ConclusionsHepatocyte-derived exosomal miR-192-5p plays a critical role in the activation of proinflammatory macrophages and disease progression of NAFLD through modulating Rictor/Akt/FoxO1 signaling. Serum exosomal miR-192-5p represents a potential noninvasive biomarker and therapeutic target for nonalcoholic steatohepatitis.

Dataset Information

Nuclear factor erythroid 2-related factor 2 regulates toll-like receptor 4 innate responses in mouse liver ischemia-reperfusion injury through Akt-forkhead box protein O1 signaling network.

Publications

Nuclear factor erythroid 2-related factor 2 regulates toll-like receptor 4 innate responses in mouse liver ischemia-reperfusion injury through Akt-forkhead box protein O1 signaling network.

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