Inhibition of NADPH oxidase promotes alternative and anti‐inflammatory microglial activation during neuroinflammation

Choi, Sangho; Aïd, Saba; Kim, Hyung‐Wook; Jackson, Sharon H.; Bosetti, Francesca

doi:10.1111/j.1471-4159.2011.07572.x

Cited by 189 publications

(159 citation statements)

References 33 publications

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“…Another possible contributing factor could arise through an absence of NOX2-mediated signaling, which may polarize macrophages toward a protective M2 (alternatively activated) phenotype. Specifically, there are two reports of a deficiency in p47 phox (Ncf) potentiating an M2-like phenotype in peritoneal macrophages or microglia in response to Listeria monocytogenes or LPS, respectively (61,62). Interestingly, macrophages deficient in gp91 phox (Cybb 2/2 ) did not show the same propensity for M2 polarization (61).…”

Section: Discussionmentioning

confidence: 99%

“…To further interrogate the ability of NOX2 to alter processing patterns of a single Ag, we measured the efficiency of WT and Cybb 2/2 BMMfs to process four distinct HEL epitopes (HEL [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] , HEL [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] , HEL [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] , and HEL 74-90 ) from whole HEL protein and present them to epitope-specific CD4 + T cell hybridomas (Hb1.9, H30.44, H46.13, and B04, respectively) (26). To achieve this, T cell hybridomas...…”

Section: Nox2 Activity Influences Mhc-ii Presentation In An Ag-specifmentioning

confidence: 99%

“…To achieve this, T cell hybridomas were first stably transfected with an NFA-T-enhanced IL-2 promoter-driven eGFP construct, followed by multiple rounds of selection by FACS to enrich those hybridoma clones that expressed eGFP only following presentation of their cognate peptide epitope by APCs (25). When added to BMMfs that were previously pulsed with HEL protein, we found that WT and Cybb 2/2 BMMfs were equally able to induce eGFP expression in two of the hybridomas (Hb1.9 and H46.13), indicating that the processing/presentation efficiency of HEL [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] and HEL [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] peptides were unaffected by NOX2 (Fig. 2D).…”

Section: Nox2 Activity Influences Mhc-ii Presentation In An Ag-specifmentioning

confidence: 99%

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NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

Allan

Tailor

Balce

et al. 2014

The Journal of Immunology

106

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The chemistries within phagosomes of APCs mediate microbial destruction as well as generate peptides for presentation on MHC class II. The antimicrobial effector NADPH oxidase (NOX2), which generates superoxide within maturing phagosomes, has also been shown to regulate activities of cysteine cathepsins through modulation of the lumenal redox potential. Using real-time analyses of lumenal microenvironmental parameters, in conjunction with hydrolysis pattern assessment of phagocytosed proteins, we demonstrated that NOX2 activity not only affects levels of phagosomal proteolysis as previously shown, but also the pattern of proteolytic digestion. Additionally, it was found that NOX2 deficiency adversely affected the ability of bone marrow–derived macrophages, but not dendritic cells, to process and present the I-Ab–immunodominant peptide of the autoantigen myelin oligodendrocyte glycoprotein (MOG). Computational and experimental analyses indicated that the I-Ab binding region of the immunodominant peptide of MOG is susceptible to cleavage by the NOX2-controlled cysteine cathepsins L and S in a redox-dependent manner. Consistent with these findings, I-Ab mice that were deficient in the p47phox or gp91phox subunits of NOX2 were partially protected from MOG-induced experimental autoimmune encephalomyelitis and displayed compromised reactivation of MOG-specific CD4+ T cells in the CNS, despite eliciting a normal primary CD4+ T cell response to the inoculated MOG Ag. Taken together, this study demonstrates that the redox microenvironment within the phagosomes of APCs is a determinant in MHC class II repertoire production in a cell-specific and Ag-specific manner, which can ultimately impact susceptibility to CD4+ T cell–driven autoimmune disease processes.

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Section: Discussionmentioning

confidence: 99%

Section: Nox2 Activity Influences Mhc-ii Presentation In An Ag-specifmentioning

confidence: 99%

Section: Nox2 Activity Influences Mhc-ii Presentation In An Ag-specifmentioning

confidence: 99%

See 1 more Smart Citation

NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

Allan

Tailor

Balce

et al. 2014

The Journal of Immunology

106

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“…NOX2 protein expression in six human PD midbrains was increased twofold in comparison to age-matched control brains, pointing to human relevance of the mouse model. Other NOX enzymes may also contribute to PD under some conditions or model systems; for example, similar approaches implicate neuronal NOX1 in PD pathogenesis in the rat 6-hydroxydopamine PD model (46) and rat paraquat PD model (51). Therefore, NOX2 and perhaps other NOX isoforms are attractive targets for slowing the progression of PD.…”

Section: Neuroinflammatory Diseasesmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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“…N-acetylcysteine has been shown to have anti-inlammatory and antioxidant actions, increasing glutathione synthesis to scavenge ROS, decreasing IL-1β and TNF-α levels in brain injury, decreasing caspase-3 levels, and shifting microglia towards M2 anti-inlammatory phenotypes [268][269][270][271].…”

Section: N-acetylcysteinementioning

confidence: 99%

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

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Inhibition of NADPH oxidase promotes alternative and anti‐inflammatory microglial activation during neuroinflammation

Cited by 189 publications

References 33 publications

NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

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