NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages.

Abstract:

:Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1β and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation.

journal_name

Nat Med

journal_title

Nature medicine

authors

Moon JS,Nakahira K,Chung KP,DeNicola GM,Koo MJ,Pabón MA,Rooney KT,Yoon JH,Ryter SW,Stout-Delgado H,Choi AM

doi

10.1038/nm.4153

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

1002-12

issue

9

eissn

1078-8956

issn

1546-170X

pii

nm.4153

journal_volume

22

pub_type

杂志文章
  • Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions.

    abstract::Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal cen...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.2426

    authors: Chung Y,Tanaka S,Chu F,Nurieva RI,Martinez GJ,Rawal S,Wang YH,Lim H,Reynolds JM,Zhou XH,Fan HM,Liu ZM,Neelapu SS,Dong C

    更新日期:2011-07-24 00:00:00

  • Cardiologist-level arrhythmia detection and classification in ambulatory electrocardiograms using a deep neural network.

    abstract::Computerized electrocardiogram (ECG) interpretation plays a critical role in the clinical ECG workflow1. Widely available digital ECG data and the algorithmic paradigm of deep learning2 present an opportunity to substantially improve the accuracy and scalability of automated ECG analysis. However, a comprehensive eval...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-018-0268-3

    authors: Hannun AY,Rajpurkar P,Haghpanahi M,Tison GH,Bourn C,Turakhia MP,Ng AY

    更新日期:2019-01-01 00:00:00

  • Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer.

    abstract::Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a singl...

    journal_title:Nature medicine

    pub_type: 杂志文章,随机对照试验

    doi:10.1038/nm1310

    authors: Rapoport AP,Stadtmauer EA,Aqui N,Badros A,Cotte J,Chrisley L,Veloso E,Zheng Z,Westphal S,Mair R,Chi N,Ratterree B,Pochran MF,Natt S,Hinkle J,Sickles C,Sohal A,Ruehle K,Lynch C,Zhang L,Porter DL,Luger S,Guo C,

    更新日期:2005-11-01 00:00:00

  • Skeletal remodeling in health and disease.

    abstract::The use of genetically manipulated mouse models, gene and protein discovery and the cataloguing of genetic mutations have each allowed us to obtain new insights into skeletal morphogenesis and remodeling. These techniques have made it possible to identify molecules that are obligatory for specific cellular functions, ...

    journal_title:Nature medicine

    pub_type: 杂志文章,评审

    doi:10.1038/nm1593

    authors: Zaidi M

    更新日期:2007-07-01 00:00:00

  • Marked amelioration of established collagen-induced arthritis by treatment with antibodies to CD23 in vivo.

    abstract::CD23 is a low-affinity receptor for immunoglobulin E (IgE) expressed by a variety of haematopoietic cells. Proteolytic cleavage of the transmembrane receptor generates soluble forms, which can be detected in biological fluids. CD23 regulates many functional aspects of immune cells, both in its cell-associated and solu...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm0895-781

    authors: Plater-Zyberk C,Bonnefoy JY

    更新日期:1995-08-01 00:00:00

  • The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.

    abstract::Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2(Brdm1) mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transport...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1163

    authors: Spanagel R,Pendyala G,Abarca C,Zghoul T,Sanchis-Segura C,Magnone MC,Lascorz J,Depner M,Holzberg D,Soyka M,Schreiber S,Matsuda F,Lathrop M,Schumann G,Albrecht U

    更新日期:2005-01-01 00:00:00

  • Cancer's true breakthroughs.

    abstract::A new regulatory pathway established last year allows drugs with dramatic early clinical promise to be expedited to the market quicker than ever before. To date, most of these 'breakthrough' designations have gone to cancer agents, raising the prospect of faster access to the latest lifesaving therapies for the estima...

    journal_title:Nature medicine

    pub_type: 新闻

    doi:10.1038/nm.3245

    authors: Dolgin E

    更新日期:2013-06-01 00:00:00

  • A cannabinoid mechanism in relapse to cocaine seeking.

    abstract::Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstat...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1001-1151

    authors: De Vries TJ,Shaham Y,Homberg JR,Crombag H,Schuurman K,Dieben J,Vanderschuren LJ,Schoffelmeer AN

    更新日期:2001-10-01 00:00:00

  • Microbiota depletion promotes browning of white adipose tissue and reduces obesity.

    abstract::Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning. Here we show that the development of functional beige fat in the ing...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.3994

    authors: Suárez-Zamorano N,Fabbiano S,Chevalier C,Stojanović O,Colin DJ,Stevanović A,Veyrat-Durebex C,Tarallo V,Rigo D,Germain S,Ilievska M,Montet X,Seimbille Y,Hapfelmeier S,Trajkovski M

    更新日期:2015-12-01 00:00:00

  • Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice.

    abstract::Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enh...

    journal_title:Nature medicine

    pub_type: 杂志文章,收录出版

    doi:10.1038/nm1117

    authors: Komazawa N,Matsuda M,Kondoh G,Mizunoya W,Iwaki M,Takagi T,Sumikawa Y,Inoue K,Suzuki A,Mak TW,Nakano T,Fushiki T,Takeda J,Shimomura I

    更新日期:2004-11-01 00:00:00

  • 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen.

    abstract::The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1641

    authors: Umetani M,Domoto H,Gormley AK,Yuhanna IS,Cummins CL,Javitt NB,Korach KS,Shaul PW,Mangelsdorf DJ

    更新日期:2007-10-01 00:00:00

  • SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses.

    abstract::Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (T(H)2) cells, but its role in T(H)2-related allergic diseases remains to be investigated. In this study we provide a strong correlation bet...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm896

    authors: Seki Y,Inoue H,Nagata N,Hayashi K,Fukuyama S,Matsumoto K,Komine O,Hamano S,Himeno K,Inagaki-Ohara K,Cacalano N,O'Garra A,Oshida T,Saito H,Johnston JA,Yoshimura A,Kubo M

    更新日期:2003-08-01 00:00:00

  • King of hearts: a splicing factor rules cardiac proteins.

    abstract::Alternative splicing ensures the expression of functionally diverse proteins from individual genes; however, aberrant mRNA splicing is associated with various conditions, including heart disease. A recent study provides new mechanistic insights into heart failure by showing that a human cardiomyopathy-linked mutation ...

    journal_title:Nature medicine

    pub_type: 评论,杂志文章

    doi:10.1038/nm.2762

    authors: Linke WA,Bücker S

    更新日期:2012-05-04 00:00:00

  • Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.

    abstract::Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two ...

    journal_title:Nature medicine

    pub_type: 杂志文章,多中心研究

    doi:10.1038/s41591-020-1085-z

    authors: van Dijk N,Gil-Jimenez A,Silina K,Hendricksen K,Smit LA,de Feijter JM,van Montfoort ML,van Rooijen C,Peters D,Broeks A,van der Poel HG,Bruining A,Lubeck Y,Sikorska K,Boellaard TN,Kvistborg P,Vis DJ,Hooijberg E,Schumac

    更新日期:2020-12-01 00:00:00

  • Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke.

    abstract::Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme gamma-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apopto...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1403

    authors: Arumugam TV,Chan SL,Jo DG,Yilmaz G,Tang SC,Cheng A,Gleichmann M,Okun E,Dixit VD,Chigurupati S,Mughal MR,Ouyang X,Miele L,Magnus T,Poosala S,Granger DN,Mattson MP

    更新日期:2006-06-01 00:00:00

  • Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing.

    abstract::With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived C...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.4355

    authors: Crespo M,Vilar E,Tsai SY,Chang K,Amin S,Srinivasan T,Zhang T,Pipalia NH,Chen HJ,Witherspoon M,Gordillo M,Xiang JZ,Maxfield FR,Lipkin S,Evans T,Chen S

    更新日期:2017-07-01 00:00:00

  • Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury.

    abstract::Traumatic spinal cord injury often results in complete loss of voluntary motor and sensory function below the site of injury. The long-term neurological deficits after spinal cord trauma may be due in part to widespread apoptosis of neurons and oligodendroglia in regions distant from and relatively unaffected by the i...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/11387

    authors: Springer JE,Azbill RD,Knapp PE

    更新日期:1999-08-01 00:00:00

  • Active movement of T cells away from a chemokine.

    abstract::Movement towards or away from a given stimulus guides the directional migration of prokaryotes, simple eukaryotes and neurons. As bi-directional cues may influence entry and exit of immune effector cells from tissue sites, we evaluated the migratory responses of T-cell subsets to varying concentrations of the chemokin...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/75022

    authors: Poznansky MC,Olszak IT,Foxall R,Evans RH,Luster AD,Scadden DT

    更新日期:2000-05-01 00:00:00

  • Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation.

    abstract::Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain el...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.2124

    authors: Rudolph V,Andrié RP,Rudolph TK,Friedrichs K,Klinke A,Hirsch-Hoffmann B,Schwoerer AP,Lau D,Fu X,Klingel K,Sydow K,Didié M,Seniuk A,von Leitner EC,Szoecs K,Schrickel JW,Treede H,Wenzel U,Lewalter T,Nickenig G,Zimmer

    更新日期:2010-04-01 00:00:00

  • The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.

    abstract::Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.2079

    authors: Guilluy C,Brégeon J,Toumaniantz G,Rolli-Derkinderen M,Retailleau K,Loufrani L,Henrion D,Scalbert E,Bril A,Torres RM,Offermanns S,Pacaud P,Loirand G

    更新日期:2010-02-01 00:00:00

  • Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia.

    abstract::T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced ne...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1524

    authors: Vilimas T,Mascarenhas J,Palomero T,Mandal M,Buonamici S,Meng F,Thompson B,Spaulding C,Macaroun S,Alegre ML,Kee BL,Ferrando A,Miele L,Aifantis I

    更新日期:2007-01-01 00:00:00

  • Aura of mystery.

    abstract::It begins as a slowly expanding spot of light or similar visual disturbance, often accompanied by phantom noises and other sensory distortions. People who experience such 'auras' know all too well that these early warning signs will culminate in a head-splitting migraine, yet scientists have little idea what causes th...

    journal_title:Nature medicine

    pub_type: 新闻

    doi:10.1038/nm0913-1083

    authors: Dolgin E

    更新日期:2013-09-01 00:00:00

  • Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

    abstract::Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an o...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-020-0827-2

    authors: Donovan LK,Delaidelli A,Joseph SK,Bielamowicz K,Fousek K,Holgado BL,Manno A,Srikanthan D,Gad AZ,Van Ommeren R,Przelicki D,Richman C,Ramaswamy V,Daniels C,Pallota JG,Douglas T,Joynt ACM,Haapasalo J,Nor C,Vladoiu MC,

    更新日期:2020-05-01 00:00:00

  • Wearable-device-measured physical activity and future health risk.

    abstract::Use of wearable devices that monitor physical activity is projected to increase more than fivefold per half-decade1. We investigated how device-based physical activity energy expenditure (PAEE) and different intensity profiles were associated with all-cause mortality. We used a network harmonization approach to map do...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-020-1012-3

    authors: Strain T,Wijndaele K,Dempsey PC,Sharp SJ,Pearce M,Jeon J,Lindsay T,Wareham N,Brage S

    更新日期:2020-09-01 00:00:00

  • IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities.

    abstract::Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1615

    authors: Orinska Z,Maurer M,Mirghomizadeh F,Bulanova E,Metz M,Nashkevich N,Schiemann F,Schulmistrat J,Budagian V,Giron-Michel J,Brandt E,Paus R,Bulfone-Paus S

    更新日期:2007-08-01 00:00:00

  • Akt2 relaxes podocytes in chronic kidney disease.

    abstract::A signaling cascade is activated in podocytes to induce survival and cope with stress during advanced glomerular disease, a new study shows. The findings may also explain why the immunosuppressor sirolimus, an inhibitor of this pathway, can cause proteinuria in a subset of patients with chronic kidney disease (pages 1...

    journal_title:Nature medicine

    pub_type: 评论,新闻

    doi:10.1038/nm.3357

    authors: Reiser J

    更新日期:2013-10-01 00:00:00

  • Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis.

    abstract::Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 in humans was discontinued because a few patients developed ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm790

    authors: McLaurin J,Cecal R,Kierstead ME,Tian X,Phinney AL,Manea M,French JE,Lambermon MH,Darabie AA,Brown ME,Janus C,Chishti MA,Horne P,Westaway D,Fraser PE,Mount HT,Przybylski M,St George-Hyslop P

    更新日期:2002-11-01 00:00:00

  • Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells.

    abstract::We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent ap...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1127

    authors: Ptasznik A,Nakata Y,Kalota A,Emerson SG,Gewirtz AM

    更新日期:2004-11-01 00:00:00

  • Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.

    abstract::Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signalin...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.3751

    authors: Yoda A,Adelmant G,Tamburini J,Chapuy B,Shindoh N,Yoda Y,Weigert O,Kopp N,Wu SC,Kim SS,Liu H,Tivey T,Christie AL,Elpek KG,Card J,Gritsman K,Gotlib J,Deininger MW,Makishima H,Turley SJ,Javidi-Sharifi N,Maciejewski

    更新日期:2015-01-01 00:00:00

  • Identification of a hormonal basis for gallbladder filling.

    abstract::The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Here we show that fibroblast growth factor-15, a hormone made by the distal small intestine in response to bile acids, is required for gallbladder filling. These studies demonstrate that gallbladder filling is act...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1501

    authors: Choi M,Moschetta A,Bookout AL,Peng L,Umetani M,Holmstrom SR,Suino-Powell K,Xu HE,Richardson JA,Gerard RD,Mangelsdorf DJ,Kliewer SA

    更新日期:2006-11-01 00:00:00