Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes

Padgett, Lindsey E.; Anderson, Brian; Liu, Chao; Ganini, Douglas; Mason, Ronald P.; Piganelli, Jon D.; Mathews, Clayton E.; Tse, Hubert M.

doi:10.2337/db15-0546

Cited by 18 publications

(20 citation statements)

References 47 publications

(85 reference statements)

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“…Here, we demonstrated that LPS/IL-4 treatment increased anti-inflammatory markers in NOX2 −/− BMDMs when compared to WT BMDMs. Unexpectedly, we observed no genotype-related change in STAT6 activation, which conflicts with a prior report showing that pSTAT6 expression is enhanced in NOX2 −/− BMDMs [44]. Such discrepancies may be due to the different activation stimuli employed in each study.…”

Section: Discussioncontrasting

confidence: 99%

“…In our model, the mixed LPS/IL-4 stimulus significantly increased pSTAT1 expression in WT and NOX2 −/− BMDMs, but STAT1 activation was significantly reduced in NOX2 −/− BMDMs. This is in agreement with a previous report where NOX deficient macrophages incubated in the presence of IFNγ/LPS exhibited decreased STAT1 activation [44]. In addition, previous work demonstrated that LPS-induced IFNβ is required for STAT1 activation [45], and this may be a mechanism that explains reduced pSTAT1 and decreased pro-inflammatory marker expression in NOX2 −/− BMDMs.…”

Section: Discussionsupporting

confidence: 93%

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NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

Barrett

Henry

Villapol

et al. 2017

J Neuroinflammation

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BackgroundNADPH oxidase (NOX2) is an enzyme system that generates reactive oxygen species (ROS) in microglia and macrophages. Excessive ROS production is linked with neuroinflammation and chronic neurodegeneration following traumatic brain injury (TBI). Redox signaling regulates macrophage/microglial phenotypic responses (pro-inflammatory versus anti-inflammatory), and NOX2 inhibition following moderate-to-severe TBI markedly reduces pro-inflammatory activation of macrophages/microglia resulting in concomitant increases in anti-inflammatory responses. Here, we report the signaling pathways that regulate NOX2-dependent macrophage/microglial phenotype switching in the TBI brain.MethodsBone marrow-derived macrophages (BMDMs) prepared from wildtype (C57Bl/6) and NOX2 deficient (NOX2−/−) mice were treated with lipopolysaccharide (LPS; 10 ng/ml), interleukin-4 (IL-4; 10 ng/ml), or combined LPS/IL-4 to investigate signal transduction pathways associated with macrophage activation using western immunoblotting and qPCR analyses. Signaling pathways and activation markers were evaluated in ipsilateral cortical tissue obtained from adult male wildtype and NOX2−/− mice that received moderate-level controlled cortical impact (CCI). A neutralizing anti-IL-10 approach was used to determine the effects of IL-10 on NOX2-dependent transitions from pro- to anti-inflammatory activation states.ResultsUsing an LPS/IL-4-stimulated BMDM model that mimics the mixed pro- and anti-inflammatory responses observed in the injured cortex, we show that NOX2−/− significantly reduces STAT1 signaling and markers of pro-inflammatory activation. In addition, NOX2−/− BMDMs significantly increase anti-inflammatory marker expression; IL-10-mediated STAT3 signaling, but not STAT6 signaling, appears to be critical in regulating this anti-inflammatory response. Following moderate-level CCI, IL-10 is significantly increased in microglia/macrophages in the injured cortex of NOX2−/− mice. These changes are associated with increased STAT3 activation, but not STAT6 activation, and a robust anti-inflammatory response. Neutralization of IL-10 in NOX2−/− BMDMs or CCI mice blocks STAT3 activation and the anti-inflammatory response, thereby demonstrating a critical role for IL-10 in regulating NOX2-dependent transitions between pro- and anti-inflammatory activation states.ConclusionsThese studies indicate that following TBI NOX2 inhibition promotes a robust anti-inflammatory response in macrophages/microglia that is mediated by the IL-10/STAT3 signaling pathway. Thus, therapeutic interventions that inhibit macrophage/microglial NOX2 activity may improve TBI outcomes by not only limiting pro-inflammatory neurotoxic responses, but also enhancing IL-10-mediated anti-inflammatory responses that are neuroprotective.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0843-4) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 93%

NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

Barrett

Henry

Villapol

et al. 2017

J Neuroinflammation

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“…As pro-inflammatory chemokine synthesis is redox-regulated [41] and (PVPON/TA) nanothin multilayer coatings can function as an antioxidant to dissipate free radicals (Figure 1 and [7]), the ability of (PVPON/TA) n to regulate pro-inflammatory chemokines implicated in islet transplant rejection within p(I:C)-stimulated BM-M ϕ was examined by qRT-PCR and ELISA. Expression of CCL5 and CXCL10 mRNA accumulation and protein expression by qRT-PCR and ELISA, respectively, was significantly lowered when p(I:C)-stimulated samples were treated with (PVPON/TA) n capsules (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…Chemokine expression was measured in the supernatants of stimulated macrophages for 72 hours as described [41]. Pro-inflammatory CCL5 and CXCL10 chemokines were detected with DuoSet ELISA kit and antibody pairs (R&D Systems) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Islet encapsulation with polyphenol coatings decreases pro-inflammatory chemokine synthesis and T cell trafficking

et al. 2017

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Type 1 Diabetes (T1D) is a chronic pro-inflammatory autoimmune disease consisting of islet-infiltrating leukocytes involved in pancreatic β-cell lysis. One promising treatment for T1D is islet transplantation; however, clinical application is constrained due to limited islet availability, adverse effects of immunosuppressants, and declining graft survival. Islet encapsulation may provide an immunoprotective barrier to preserve islet function and prevent immune-mediated rejection after transplantation. We previously demonstrated that a novel cytoprotective nanothin multilayer coating for islet encapsulation consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), was efficacious in dampening in vitro immune responses involved in transplant rejection and preserving in vitro islet function. However, the ability of (PVPON/TA) to maintain islet function in vivo and reverse diabetes has not been tested. Recent evidence has demonstrated that modulation of redox status can affect pro-inflammatory immune responses. Therefore, we hypothesized that transplanted (PVPON/TA)-encapsulated islets can restore euglycemia to diabetic mice and provide an immunoprotective barrier. Our results demonstrate that (PVPON/TA) nanothin coatings can significantly decrease in vitro chemokine synthesis and diabetogenic T cell migration. Importantly, (PVPON/TA)-encapsulated islets restored euglycemia after transplantation into diabetic mice. Our results demonstrate that (PVPON/TA)-encapsulated islets may suppress immune responses and enhance islet allograft acceptance in patients with T1D.

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“…Interestingly, although NOD mice are normally resistant to EAE, 91 they display strong disease in the absence of Ncf1. Moreover, by using Ncf1 m1J mutated mice 51 harboring a single autoreactive T‐cell clone from a NOD mouse ( BDC‐2.5.Ncf1 m1J ), 92 a reduced Treg suppressive capacity became apparent, inducing diabetes during both spontaneous and adoptive transfer of T1D 93 . Also, an increased production of pro‐inflammatory cytokines, like TNF‐α, IL‐17A and IFN‐γ is detected by BDC‐2.5.Ncf1 m1J cells in vitro confirming the contribution of both T H 1 and T H 17 to T1D pathology.…”

Section: Type I Diabetesmentioning

confidence: 99%

Immunometabolism and autoimmunity

et al. 2016

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A continuous increase in the prevalence of autoimmune diseases is to be expected in the aging societies worldwide. Autoimmune disorders not only cause severe disability and chronic pain, but also lead to considerable socio-economic costs. Given that the current treatment options are not curative, have substantial side effects and a high percentage of non-responders, innovative options to the existing therapeutic armament against autoimmune diseases are urgently required. Accumulating evidence suggests that changes in the metabolism of immune cells are associated with, and contribute to the pathogenesis of autoimmunity. Additionally, some autoimmune diseases share alterations in metabolic pathways, key metabolites or metabolic byproducts such as reactive oxygen species. Other examples for metabolic changes in autoimmune settings include modifications in amino acid and cholesterol levels or glucose catabolism. Thus, the emerging field of immunometabolism may hold the potential to discover new therapeutic targets. Here, we discuss recent findings describing metabolic changes in autoimmune arthritis, multiple sclerosis as well as type 1 diabetes, focusing on pathophysiological aspects.

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Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes

Cited by 18 publications

References 47 publications

NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

Islet encapsulation with polyphenol coatings decreases pro-inflammatory chemokine synthesis and T cell trafficking

Immunometabolism and autoimmunity

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