Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation

Cuadrado, Antonio; Martín‐Moldes, Zaira; Ye, Jianping; Lastres‐Becker, Isabel

doi:10.1074/jbc.m113.540633

Cited by 261 publications

(181 citation statements)

References 48 publications

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“…However, knockdown of Rac1 in CECs did not reduce TNF-aemediated NF-kB activation, providing evidence that TNF-aeinduced activation of NF-kB, mediated by NADPH oxidase, generated ROS upstream of Rac1 activation. These findings suggest additional regulatory mechanisms from those recently reported, 35 in which NF-kB activation during inflammation was found downstream of Rac1.…”

Section: Rap1 Inhibits Tnf-aeinduced Ros Signalssupporting

confidence: 74%

Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Wang

Fotheringham

Wittchen

et al. 2015

The American Journal of Pathology

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Macrophage-derived tumor necrosis factor (TNF)-a has been found in choroidal neovascularization (CNV) surgically removed from patients with age-related macular degeneration. However, the role of TNF-a in CNV development remains unclear. In a murine laser-induced CNV model, compared with un-lasered controls, TNF-a mRNA was increased in retinal pigment epithelial and choroidal tissue, and TNF-a colocalized with lectin-stained migrating choroidal endothelial cells (CECs). Inhibition of TNF-a with a neutralizing antibody reduced CNV volume and reactive oxygen species (ROS) level around CNV. In CECs, pretreatment with the antioxidant apocynin or knockdown of p22phox, a subunit of NADPH oxidase, inhibited TNF-aeinduced ROS generation. Apocynin reduced TNF-aeinduced NF-kB and Rac1 activation, and inhibited TNF-aeinduced CEC migration. TNF-aeinduced Rac1 activation and CEC migration were inhibited by NF-kB inhibitor Bay11-7082. Overexpression of Rap1a prevented TNF-aeinduced ROS generation and reduced NF-kB and Rac1 activation. Activation of Rap1 by 8-(4-chlorophenylthio) adenosine-2 0 -O-Me-cAMP prevented TNF-aeinduced CEC migration and reduced laser-induced CNV volume, ROS generation, and activation of NF-kB and Rac1. These findings provide evidence that active Rap1a inhibits TNF-aeinduced CEC migration by inhibiting NADPH oxidase-dependent NF-kB and Rac1 activation and suggests that Rap1a de-escalates CNV development by interfering with ROSdependent signaling in several steps of the pathogenic process. One reason may be that treatment is provided too late when CNV is already present. To address this possibility, we focus on understanding early steps in the pathophysiology in neovascular AMD to prevent vision loss. Activation and migration of choroidal endothelial cells (CECs) are early steps in the development of CNV. Activated CECs migrate through the Bruch membrane toward the retinal pigment epithelium (RPE) and also transmigrate the RPE into the sensory retina. At either location, activated CECs can proliferate to form CNV. Severe vision loss occurs when CNV develops in the sensory retina. 3,4 Both inflammation and oxidative stress have been implicated in the development of CNV.

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Section: Rap1 Inhibits Tnf-aeinduced Ros Signalssupporting

confidence: 74%

Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Wang

Fotheringham

Wittchen

et al. 2015

The American Journal of Pathology

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“…354 Cuadrado et al 2014). Consistently, in NRF2-deficient (Nrf2 2/2 ) mice challenged with LPS or tumor necrosis factor (TNF)-a, the activity of IKK was exacerbated and led to increased phosphorylation and degradation of IkB (Thimmulappa et al, 2006a).…”

Section: A Key Role Of Nuclear Factor (Erythroid-derived 2)-like 2 Imentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…However, oxidation of cysteines in KEAP1 relieves binding and allows Nrf2 to accumulate, enter the nucleus and exert its activity (Zhang and Hannink, 2003;Zhang et al, 2004;Yamamoto et al, 2008). It therefore also follows that inherent to M1 activation and increased NOX2 activity, there is a certain level of Nrf2 activation and induction of antioxidant proteins (Kim et al, 2010;Kong et al, 2010), which again opposes NF-kB activity (Kong et al, 2010;Cuadrado et al, 2014) and oxidant levels to uphold redox homeostasis. Although timing is crucial, there is a broad assumption that acquisition of the M2 phenotype is beneficial in acute or chronic brain disease (Cherry et al, 2014;Hu et al, 2015).…”

mentioning

confidence: 99%

Microglia antioxidant systems and redox signalling

Vilhardt¹,

Haslund-vinding

Jaquet³

et al. 2016

British J Pharmacology

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For many years, microglia, the resident CNS macrophages, have been considered only in the context of pathology, but microglia are also glial cells with important physiological functions. Microglia-derived oxidant production by NADPH oxidase (NOX2) is implicated in many CNS disorders. Oxidants do not stand alone, however, and are not always pernicious. We discuss in general terms, and where available in microglia, GSH synthesis and relation to cystine import and glutamate export, and the thioredoxin system as the most important antioxidative defence mechanism, and further, we discuss in the context of protein thiolation of target redox proteins the necessity for tightly localized, timed and confined oxidant production to work in concert with antioxidant proteins to promote redox signalling. NOX2-mediated redox signalling modulates the acquisition of the classical or alternative microglia activation phenotypes by regulating major transcriptional programs mediated through NF-κB and Nrf2, major regulators of the inflammatory and antioxidant response respectively. As both antioxidants and NOX-derived oxidants are co-secreted, in some instances redox signalling may extend to neighboring cells through modification of surface or cytosolic target proteins. We consider a role for microglia NOX-derived oxidants in paracrine modification of synaptic function through long term depression and in the communication with the adaptive immune system. There is little doubt that a continued foray into the functions of the antioxidant response in microglia will reveal antioxidant proteins as dynamic players in redox signalling, which in concert with NOX-derived oxidants fulfil important roles in the autocrine or paracrine regulation of essential enzymes or transcriptional programs. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations Aβ, amyloid-β peptide 1-42; DAMP, damage-associated molecular pattern molecules; GCL, glutamate cysteine ligase; GPx, GSH peroxidase; HNE, 4-hydroxy-2-nonenal; HO-1, haem oxygenase-1; KEAP1, Kelch-like ECH-associated protein; LTD, long-term depression; PLA 2 , phospholipase A 2 ; Prx, peroxiredoxins; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, cystine-glutamate exchanger IntroductionMicroglia, the resident immune cells of the brain, are exquisitely sensitive cells, which through a large and unique repertoire of sensing cell surface receptors (Hickman et al., 2013) responding to ligands of exogenous or endogenous nature (Kettenmann et al., 2013) continuously survey the brain parenchyma for even the smallest deviation from homeostasis. When the fine, motile processes of microglia encounter a problem, microglia assume an activation phenotype adapted to the quick resolution of damage and return to homeostasis. If instigating insults cannot be resolved, chronic microglia activation ensues. The differing nature of...

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Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation

Cited by 261 publications

References 48 publications

Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Microglia antioxidant systems and redox signalling

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