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 Medjournal_title
Nature medicineauthors
Moon JS,Nakahira K,Chung KP,DeNicola GM,Koo MJ,Pabón MA,Rooney KT,Yoon JH,Ryter SW,Stout-Delgado H,Choi AMdoi
10.1038/nm.4153subject
Has Abstractpub_date
2016-09-01 00:00:00pages
1002-12issue
9eissn
1078-8956issn
1546-170Xpii
nm.4153journal_volume
22pub_type
杂志文章相关文献
NATURE MEDICINE文献大全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
更新日期:2011-07-24 00:00:00
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
更新日期:2019-01-01 00:00:00
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
更新日期:2005-11-01 00:00:00
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
更新日期:2007-07-01 00:00:00
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
更新日期:1995-08-01 00:00:00
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
更新日期:2005-01-01 00:00:00
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
更新日期:2013-06-01 00:00:00
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
更新日期:2001-10-01 00:00:00
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
更新日期:2015-12-01 00:00:00
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
更新日期:2004-11-01 00:00:00
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
更新日期:2007-10-01 00:00:00
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
更新日期:2003-08-01 00:00:00
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
更新日期:2012-05-04 00:00:00
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
更新日期:2020-12-01 00:00:00
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
更新日期:2006-06-01 00:00:00
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
更新日期:2017-07-01 00:00:00
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
更新日期:1999-08-01 00:00:00
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
更新日期:2000-05-01 00:00:00
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
更新日期:2010-04-01 00:00:00
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
更新日期:2010-02-01 00:00:00
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
更新日期:2007-01-01 00:00:00
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
更新日期:2013-09-01 00:00:00
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
更新日期:2020-05-01 00:00:00
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
更新日期:2020-09-01 00:00:00
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
更新日期:2007-08-01 00:00:00
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
更新日期:2013-10-01 00:00:00
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
更新日期:2002-11-01 00:00:00
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
更新日期:2004-11-01 00:00:00
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
更新日期:2015-01-01 00:00:00
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
更新日期:2006-11-01 00:00:00