scholarly journals ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2962
Author(s):  
Anna Santarsiero ◽  
Paolo Convertini ◽  
Simona Todisco ◽  
Ciro L. Pierri ◽  
Anna De Grassi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Lipoteichoic Acid ◽  
Metabolic Reprogramming ◽  
Metabolic Enzyme ◽  
Atp Citrate Lyase ◽  
Proinflammatory Response ◽  
Proinflammatory Gene ◽  
Molecular Patterns

Macrophage stimulation by pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) or lipoteichoic acid (LTA) drives a proinflammatory phenotype and induces a metabolic reprogramming to sustain the cell’s function. Nevertheless, the relationship between metabolic shifts and gene expression remains poorly explored. In this context, the metabolic enzyme ATP citrate lyase (ACLY), the producer of citrate-derived acetyl-coenzyme A (CoA), plays a critical role in supporting a proinflammatory response. Through immunocytochemistry and cytosol–nucleus fractionation, we found a short-term ACLY nuclear translocation. Protein immunoprecipitation unveiled the role of nuclear ACLY in NF-κB acetylation and in turn its full activation in human PBMC-derived macrophages. Notably, sepsis in the early hyperinflammatory phase triggers ACLY-mediated NF-κB acetylation. The ACLY/NF-κB axis increases the expression levels of proinflammatory genes, including SLC25A1—which encodes the mitochondrial citrate carrier—and ACLY, thus promoting the existence of a proinflammatory loop involving SLC25A1 and ACLY genes.

scholarly journals Zygomycetes Hyphae Trigger an Early, Robust Proinflammatory Response in Human Polymorphonuclear Neutrophils through Toll-Like Receptor 2 Induction but Display Relative Resistance to Oxidative Damage

2007 ◽  
Vol 52 (2) ◽  
pp. 722-724 ◽  
Author(s):  
G. Chamilos ◽  
R. E. Lewis ◽  
G. Lamaris ◽  
T. J. Walsh ◽  
D. P. Kontoyiannis
Keyword(s):  
Gene Expression ◽  
Oxidative Damage ◽  
Rhizopus Oryzae ◽  
Polymorphonuclear Neutrophils ◽  
Toll Like Receptor ◽  
Relative Resistance ◽  
Proinflammatory Response ◽  
Proinflammatory Gene ◽  
Toll Like Receptor 2 ◽  
Proinflammatory Gene Expression

ABSTRACT Human polymorphonuclear neutrophils (HPMNs) displayed attenuated hyphal damage associated with impaired O2 − release following exposure to Rhizopus oryzae versus that with Aspergillus fumigatus. Exposure of HPMNs to R. oryzae hyphae resulted in upregulation in Toll-like receptor 2 mRNA and a robust proinflammatory gene expression with rapid (1-h) induction of NF-κB pathway-related genes.

scholarly journals Histone deacetylase 2–mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression

2005 ◽  
Vol 203 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Kazuhiro Ito ◽  
Satoshi Yamamura ◽  
Sarah Essilfie-Quaye ◽  
Borja Cosio ◽  
Misako Ito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Histone Deacetylase ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Site Directed Mutagenesis ◽  
Chronic Obstructive ◽  
Histone Deacetylase Inhibition ◽  
Histone Deacetylase 2

Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.

PECAM-1-dependent heme oxygenase-1 regulation via an Nrf2-mediated pathway in endothelial cells

2014 ◽  
Vol 111 (06) ◽  
pp. 1077-1088 ◽  
Author(s):  
Yarúa Jaimes ◽  
Ananta Paine ◽  
Constanca Figueiredo ◽  
Britta Eiz-Vesper ◽  
Rainer Blasczyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Chinese Hamster ◽  
Human Neutrophils ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Functional Link

SummaryThe antioxidant enzyme heme oxygenase (HO)-1, which catalyses the first and rate-limiting step of heme degradation, has major anti-inflammatory and immunomodulatory effects via its cell-type-specific functions in the endothelium. In the current study, we investigated whether the key endothelial adhesion and signalling receptor PECAM-1 (CD31) might be involved in the regulation of HO-1 gene expression in human endothelial cells (ECs). To this end PECAM-1 expression was down-regulated in human umbilical vein ECs (HUVECs) by an adenoviral vector-based knockdown approach. PECAM-1 knockdown markedly induced HO-1, but not the constitutive HO isoform HO-2. Nuclear translocation of the transcription factor NF-E2-related factor-2 (Nrf2), which is a master regulator of the inducible antioxidant cell response, and intracellular levels of reactive oxygen species (ROS) were increased in PECAM-1-deficient HUVECs, respectively. PECAM-1-dependent HO-1 regulation was also examined in PECAM-1 over-expressing Chinese hamster ovary and murine L-cells. Endogenous HO-1 gene expression and reporter gene activity of transiently transfected luciferase HO-1 promoter constructs with Nrf2 target sequences were decreased in PECAM-1 over-expressing cells. Moreover, a regulatory role of ROS for HO-1 regulation in these cells is demonstrated by studies with the antioxidant N-acetylcysteine and exogenous hydrogenperoxide. Finally, direct interaction of PECAM-1 with a native complex of its binding partner NB1 (CD177) and serine proteinase 3 (PR3) from human neutrophils, markedly induced HO-1 expression in HUVECs. Taken together, we demonstrate a functional link between HO-1 gene expression and PECAM-1 in human ECs, which might play a critical role in the regulation of inflammation.

scholarly journals TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Fanglong Wu ◽  
Shimeng Wang ◽  
Qingxiang Zeng ◽  
Junjiang Liu ◽  
Jin Yang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Oral Cancer ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
Cancer Associated Fibroblasts

AbstractCancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.

scholarly journals Novel Roles of Necroptosis Mediator Receptor-Interacting Protein Kinase 3 in Kidney Injury

Nephron ◽  
2021 ◽  
pp. 1-5
Author(s):  
Rie Uni ◽  
Mary E. Choi
Keyword(s):  
Protein Kinase ◽  
Critical Role ◽  
Kidney Injury ◽  
Metabolic Enzyme ◽  
Tubular Injury ◽  
Atp Citrate Lyase ◽  
Interacting Protein ◽  
Kidney Fibrosis ◽  
Membrane Rupture ◽  
Regulated Necrosis

Necroptosis is a programmed cell death that is characterized by regulated necrosis resulting in plasma membrane rupture and subsequent release of damage-associated molecular patterns (DAMPs). Receptor-interacting protein kinase 3 (RIPK3) is a key mediator of this pathway. Accumulating evidence supports a critical role of RIPK3 and the necroptosis pathway in various human diseases. In this review, we discuss recent investigations that have uncovered pathogenic roles of RIPK3 in both acute kidney injury (AKI) and kidney fibrosis. RIPK3 promotes kidney tubular injury via a mechanism involving mitochondrial dysfunction. Additionally, extracellular mitochondrial DNA, which is one of the necroptotic DAMPs, released from damaged mitochondria correlates with kidney tubular injury and represents a potential novel biomarker. RIPK3 also induces kidney fibrogenesis through AKT-dependent activation of the metabolic enzyme ATP citrate lyase. Thus, the RIPK3-mediated necroptosis pathway may serve as a promising new therapeutic target in AKI and kidney fibrosis.

scholarly journals Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice

2021 ◽  
Vol 118 (7) ◽  
pp. e2021862118
Author(s):  
Xiangqin He ◽  
Kunzhe Dong ◽  
Jian Shen ◽  
Guoqing Hu ◽  
Jinhua Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
High Mobility Group ◽  
No Production ◽  
High Mobility Group Protein ◽  
Pulmonary Vascular Permeability ◽  
Proinflammatory Gene

Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPS-induced proinflammatory gene expression in cultured macrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis.

scholarly journals Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway

2020 ◽  
Vol 127 (4) ◽  
pp. 534-549 ◽  
Author(s):  
Yan You ◽  
Wei-Lian Bao ◽  
Su-Lin Zhang ◽  
Hai-Dong Li ◽  
Hui Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Myeloid Cell ◽  
Metabolic Reprogramming ◽  
Foam Cell Formation ◽  
Sorting Nexin ◽  
Atherosclerotic Lesions ◽  
Mitochondrial Fatty Acid ◽  
Anti Inflammatory

Rationale: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. Objective: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. Methods and Results: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE −/− (apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE −/− mice. Myeloid cell-specific SNX10 deficiency (Δ knockout [KO]) attenuated atherosclerosis progression in APOE −/− mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. Conclusions: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.

THRAP3 depletion reduces PPARγ mRNA and anti-inflammatory action in 3T3-L1 adipocytes

2021 ◽  
Author(s):  
Juu-Chin Lu ◽  
Chia-Yun Lu ◽  
Ying-Yu Wu
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Proinflammatory Response ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Erk Phosphorylation ◽  
Proinflammatory Gene ◽  
Anti Inflammatory ◽  
Proinflammatory Gene Expression

Peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator of adipocytes and the cellular target of thiazolidinedione (TZD) drugs. Suppression of proinflammatory actions, including proinflammatory gene expression and lipolysis in adipocytes, contributes to PPARγ-mediated anti-diabetic effects of TZDs. However, adverse side effects largely limited the clinical use of TZDs, despite their potent insulin-sensitizing effects. Therefore, it is important to understand how PPARγ is regulated. Thyroid hormone receptor-associated protein 3 (THRAP3) was previously reported to promote diabetic gene expression by acting as a transcriptional coregulator of PPARγ in adipocytes. Therefore, we tested if THRAP3 modulated anti-inflammatory functions of PPARγ in 3T3-L1 adipocytes. THRAP3 depletion increased basal and tumor necrosis factor α (TNFα)-induced lipolysis, proinflammatory gene expression, and phosphorylation of extracellular signal-regulated kinases (ERKs), suggesting elevated proinflammatory response after THRAP3 depletion in adipocytes. Moreover, TZD-mediated suppression of TNFα-induced lipolysis, proinflammatory gene expression, and ERK phosphorylation were attenuated or alleviated after THRAP3 depletion. Interestingly, the mRNA and protein levels of PPARγ were greatly reduced in THRAP3-depleted adipocytes. Actinomycin D treatment revealed that the stability of PPARγ mRNA was greatly reduced by THRAP3 depletion in adipocytes. Thus, in addition to modulating PPARγ function, THRAP3 may directly regulate the transcript of PPARγ in differentiated adipocytes.

scholarly journals Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiean Xu ◽  
Lina Wang ◽  
Qiuhua Yang ◽  
Qian Ma ◽  
Yaqi Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Dysfunction ◽  
Aerobic Glycolysis ◽  
Interleukin 1 ◽  
Critical Role ◽  
Glycolytic Flux ◽  
Lung Edema ◽  
Proinflammatory Gene ◽  
Proinflammatory Gene Expression

Sepsis, a pathology resulting from excessive inflammatory response that leads to multiple organ failure, is a major cause of mortality in intensive care units. Macrophages play an important role in the pathophysiology of sepsis. Accumulating evidence has suggested an upregulated rate of aerobic glycolysis as a key common feature of activated proinflammatory macrophages. Here, we identified a crucial role of myeloid 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a glycolytic activator in lipopolysaccharide (LPS)-induced endotoxemia in mice. Pfkfb3 expression is substantially increased in bone marrow derived macrophages (BMDMs) treated with LPS in vitro and in lung macrophages of mice challenged with LPS in vivo. Myeloid-specific knockout of Pfkfb3 in mice protects against LPS-induced lung edema, cardiac dysfunction and hypotension, which were associated with decreased expression of interleukin 1 beta (Il1b), interleukin 6 (Il6) and nitric oxide synthase 2 (Nos2), as well as reduced infiltration of neutrophils and macrophages in lung tissue. Pfkfb3 ablation in cultured macrophages attenuated LPS-induced glycolytic flux, resulting in a decrease in proinflammatory gene expression. Mechanistically, Pfkfb3 ablation or inhibition with a Pfkfb3 inhibitor AZ26 suppresses LPS-induced proinflammatory gene expression via the NF-κB signaling pathway. In summary, our study reveals the critical role of Pfkfb3 in LPS-induced sepsis via reprogramming macrophage metabolism and regulating proinflammatory gene expression. Therefore, PFKFB3 is a potential target for the prevention and treatment of inflammatory diseases such as sepsis.

scholarly journals A PPARγ agonist reduces proinflammatory cytokine immunoreactivity and infarct size following transient focal ischemia in rats

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 354-354
Author(s):  
Sophia Sundararajan ◽  
W David Lust ◽  
Gary E Landreth
Keyword(s):  
Gene Expression ◽  
Infarct Size ◽  
Infarct Volume ◽  
Critical Role ◽  
Ischemic Injury ◽  
Nuclear Hormone Receptor ◽  
Markers Of Inflammation ◽  
Pparγ Agonist ◽  
Proinflammatory Gene ◽  
Proinflammatory Gene Expression

P82 Inflammation plays a critical role in the generation of ischemic injury. Ischemic insult results in the activation of microglia and secretion of proinflammatory products including the cytokines interleukin-1β and tumor necrosis factor-α. Both of these cytokines exacerbate ischemic injury. Microglial proinflammatory gene expression is regulated by the transcription factor peroxisome proliferator activated receptor (PPAR). PPARγ is a member of the nuclear hormone receptor family and upon binding of agonist acts to inhibit proinflammatory gene expression. We hypothesized that PPARγ agonists reduce the inflammatory reaction seen following stroke and limit infarction size. We utilized a reversible model of middle cerebral artery occlusion to induce two hours of ischemia in rats to test our hypothesis. Blood pressure, blood gases and temperature were monitored and maintained within normal ranges throughout the procedure. Vehicle (DMSO) or troglitazone, a PPARγ agonist previously approved by the FDA, was administered to rats twenty-four hours before and again at the time of occlusion in doses of 35, 70 or 100 mg/kg in DMSO. Twenty-four hours after occlusion animals were euthanized. Infarct volume was calculated from fixed frozen sections and additional sections were processed for immunocytochemistry. Results show over sixty percent reduction in infarct volume in rats treated with 35 mg/kg and 70 mg/kg troglitazone. These data were statistically significant (n≥5;p<0.05). Interestingly the 100 mg/kg dose of troglitazone did not protect against ischemia. Immunoreactivity against the proinflammatory cytokines Il-1β and TNFα was reduced in the peri-infarct region of troglitazone treated rats. Furthermore, immunoreactivity against other markers of inflammation, intracellular adhesion molecule, major histocompatibility complex antigen I and cyclooxygenase-2 was also reduced in troglitazone treated animals compared with vehicle treated animals. These data indicate that the PPARγ agonist, troglitazone, reduces infarct size following cerebral ischemia likely due to the drug’s anti-inflammatory properties.

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