NADPH oxidases in oxidant production by microglia: activating receptors, pharmacology and association with disease

Haslund-vinding, Jepper Lohfert; McBean, Gethin J.; Jaquet, Vincent; Vilhardt, Frédérik

doi:10.1111/bph.13425

Cited by 125 publications

(95 citation statements)

References 229 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to RSV’s potent anti-inflammatory effects, it has also been suggested to inhibit nuclear factor kappa B through histone deacetylation by SIRT-1 (Bagul et al, 2015; Borra et al, 2005), a factor which has been linked to the development of depressive-like states (Haslund-Vinding et al, 2016; Patki et al, 2013b; Vilhardt et al, 2016). In the present study there were no differences in SIRT-1 protein levels between stress or treatment groups.…”

Section: Discussionmentioning

confidence: 99%

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior

Finnell

Lombard

Melson

et al. 2017

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

Social stress is a risk factor for psychiatric disorders, however only a subset of the population is susceptible while others remain resilient. Inflammation has been linked to the pathogenesis of psychosocial disorders in humans and may underlie these individual differences. Using a resident-intruder paradigm capable of revealing individual differences in coping behavior and inflammatory responses, the present study determined if resveratrol (RSV; 0, 10, 30mg/kg/day) protected against persistent stress-induced inflammation in socially defeated rats. Furthermore, the antidepressant efficacy of RSV was evaluated using the sucrose preference test. Active coping rats were characterized by more time spent in upright postures and increased defeat latencies versus passive coping rats. Five days after defeat, flow cytometry revealed enhanced stimulation of inflammatory proteins (IL-β, TNF-α) in spleen cells of passive rats as compared to active coping and controls, an effect that was blocked by both doses of RSV. Furthermore, only passive coping rats exhibited increased proinflammatory proteins (IL-1β, TNF-α, GM-CSF) in the locus coeruleus (LC), a noradrenergic brain region implicated in depression. Notably, only 30mg/kg RSV blocked LC neuroinflammation and importantly, was the only dose that blocked anhedonia. Alternatively, while stress had minimal impact on resting cytokines in the dorsal raphe (DR), RSV dose-dependently reduced DR cytokine expression. However, this did not result in changes in indoleamine 2,3-dioxygenase activity or serotonin levels. Taken together, these data suggest that social stress-induced depressive-like behavior evident in passive coping rats may be driven by stress-induced neuroinflammation and highlight natural anti-inflammatory agents to protect against social stress-related consequences.

show abstract

Section: Discussionmentioning

confidence: 99%

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior

Finnell

Lombard

Melson

et al. 2017

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

show abstract

“…A large cohort of studies support the notion that release of H 2 O 2 from cell surface-resident NOX can diffuse back into the cytosol to effect physiological redox signalling, subsequent to cell surface receptor activation. This autocrine function of secreted ROS is discussed in detail in the accompanying review (Haslund-Vinding et al, 2017), while we here discuss the potential paracrine role of ROS and antioxidants. While the diffusion range of H 2 O 2 in the highly reducing cytosol is limited to a few micrometers (Mishina et al, 2011), the diffusion range is considerably extended in the extracellular space.…”

Section: Paracrine Effects Of Ros and Antioxidantsmentioning

confidence: 95%

“…In combination with the accompanying review (Haslund-Vinding et al, 2017), we place the emphasis on the family of NADPH oxidases (NOX family) in oxidant production, and the GSH-thioredoxin antioxidant system required for the transient thiol modification of target proteins for signalling purposes. We refer the interested reader to a detailed review for discussion of other antioxidant systems in microglia (Dringen, 2005).…”

Section: Bjpmentioning

confidence: 99%

“…Their regulated production of superoxide and hydrogen peroxide through the one electron reduction of molecular oxygen (Bedard and Krause, 2007) has been implicated as essential in different types of acute and chronic brain disease (Nayernia et al, 2014). We refer to the accompanying review for a more detailed description of the NOX family in microglia (Haslund-Vinding et al, 2017). First recognized for the role of the classical phagocyte NADPH oxidase (NOX2) in production of superoxide and derived oxidants in neutrophilpathogen combat, NOX-produced hydrogen peroxide is now known to participate in redox regulation of a great number of different proteins through the transient and reversible oxidation of target protein cysteines to produce typically sulphenic acid or S-glutathionylated protein adducts (Winterbourn, 2013;Holmstrom and Finkel, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Microglia antioxidant systems and redox signalling

Vilhardt¹,

Haslund-vinding

Jaquet³

et al. 2016

British J Pharmacology

Self Cite

105

View full text Add to dashboard Cite

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...

show abstract

“…NOX2 is thought to be latent under normal conditions; upon microglial activation, NOX2 becomes activated through the formation of a multimeric protein complex leading to NOX2-derived superoxide formation. 5 This activation process is thought to play a key role in mediating proinflammatory, M1-polarized microglia in neuroinflammation, and increases in the levels of NOX2 and other markers of oxidative stress have been reported in post-mortem samples of Alzheimer’s disease (AD) brain and in transgenic mouse models of AD. 4,6 Similar results have been reported in the substantia nigra of PD brain samples and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD.…”

Section: Introductionmentioning

confidence: 99%

Development of a Positron Emission Tomography Radiotracer for Imaging Elevated Levels of Superoxide in Neuroinflammation

Hou

Hsieh

et al. 2017

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Reactive oxygen species (ROS) are believed to play a major role in the proinflammatory, M1-polarized form of neuroinflammation. However, it has been difficult to assess the role of ROS and their role in neuroinflammation in animal models of disease because of the absence of probes capable of measuring their presence with the functional imaging technique positron emission tomography (PET). This study describes the synthesis and in vivo evaluation of [18F]ROStrace, a radiotracer for imaging superoxide in vivo with PET, in an LPS model of neuroinflammation. [18F]ROStrace was found to rapidly cross the blood–brain barrier (BBB) and was trapped in the brain of LPS-treated animals but not the control group. [18F]ox-ROStrace, the oxidized form of [18F]ROStrace, did not cross the BBB. These data suggest that [18F]ROStrace is a suitable radiotracer for imaging superoxide levels in the central nervous system with PET.

show abstract

NADPH oxidases in oxidant production by microglia: activating receptors, pharmacology and association with disease

Cited by 125 publications

References 229 publications

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior

Microglia antioxidant systems and redox signalling

Development of a Positron Emission Tomography Radiotracer for Imaging Elevated Levels of Superoxide in Neuroinflammation

Contact Info

Product

Resources

About