Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

Silvia Cellone Trevelin; Célio Xavier Dos Santos; Raphael Gomes Ferreira; Larissa de Sá Lima; Rangel Leal Silva; Cristoforo Scavone; Rui Curi; José Carlos Alves-Filho; Thiago Mattar Cunha; Pérsio Roxo-Júnior; Maria-Célia Cervi; Francisco Rafael Martins Laurindo; John Stephen Hothersall; Andrew M Cobb; Min Zhang; Aleksandar Ivetic; Ajay M Shah; Lucia Rossetti Lopes; Fernando Queiroz Cunha

doi:10.1038/srep34581

Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

Silvia Cellone Trevelin, Célio Xavier Dos Santos, Raphael Gomes Ferreira, Larissa de Sá Lima, Rangel Leal Silva, Cristoforo Scavone, Rui Curi, José Carlos Alves-Filho, Thiago Mattar Cunha, Pérsio Roxo-Júnior, Maria-Célia Cervi, Francisco Rafael Martins Laurindo, John Stephen Hothersall, Andrew M Cobb, Min Zhang, Aleksandar Ivetic, Ajay M Shah, Lucia Rossetti Lopes, Fernando Queiroz Cunha

Cardiovascular Sciences

University of Sao Paulo

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.

Original language	English
Article number	34581
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep34581
Publication status	Published - 4 Oct 2016

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10.1038/srep34581Licence: CC BY

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Trevelin, S. C., Dos Santos, C. X., Ferreira, R. G., de Sá Lima, L., Silva, R. L., Scavone, C., Curi, R., Alves-Filho, J. C., Cunha, T. M., Roxo-Júnior, P., Cervi, M.-C., Laurindo, F. R. M., Hothersall, J. S., Cobb, A. M., Zhang, M., Ivetic, A., Shah, A. M., Lopes, L. R., & Cunha, F. Q. (2016). Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state. Scientific Reports, 6, Article 34581. https://doi.org/10.1038/srep34581

@article{ed5d7f9934344cd49f57ae62b8a73146,

title = "Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state",

abstract = "The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.",

author = "Trevelin, {Silvia Cellone} and {Dos Santos}, {C{\'e}lio Xavier} and Ferreira, {Raphael Gomes} and {de S{\'a} Lima}, Larissa and Silva, {Rangel Leal} and Cristoforo Scavone and Rui Curi and Alves-Filho, {Jos{\'e} Carlos} and Cunha, {Thiago Mattar} and P{\'e}rsio Roxo-J{\'u}nior and Maria-C{\'e}lia Cervi and Laurindo, {Francisco Rafael Martins} and Hothersall, {John Stephen} and Cobb, {Andrew M} and Min Zhang and Aleksandar Ivetic and Shah, {Ajay M} and Lopes, {Lucia Rossetti} and Cunha, {Fernando Queiroz}",

year = "2016",

month = oct,

day = "4",

doi = "10.1038/srep34581",

language = "English",

volume = "6",

journal = "Scientific Reports",

issn = "2045-2322",

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Trevelin, SC, Dos Santos, CX, Ferreira, RG, de Sá Lima, L, Silva, RL, Scavone, C, Curi, R, Alves-Filho, JC, Cunha, TM, Roxo-Júnior, P, Cervi, M-C, Laurindo, FRM, Hothersall, JS, Cobb, AM , Zhang, M , Ivetic, A , Shah, AM, Lopes, LR & Cunha, FQ 2016, 'Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state', Scientific Reports, vol. 6, 34581. https://doi.org/10.1038/srep34581

TY - JOUR

T1 - Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

AU - Trevelin, Silvia Cellone

AU - Dos Santos, Célio Xavier

AU - Ferreira, Raphael Gomes

AU - de Sá Lima, Larissa

AU - Silva, Rangel Leal

AU - Scavone, Cristoforo

AU - Curi, Rui

AU - Alves-Filho, José Carlos

AU - Cunha, Thiago Mattar

AU - Roxo-Júnior, Pérsio

AU - Cervi, Maria-Célia

AU - Laurindo, Francisco Rafael Martins

AU - Hothersall, John Stephen

AU - Cobb, Andrew M

AU - Zhang, Min

AU - Ivetic, Aleksandar

AU - Shah, Ajay M

AU - Lopes, Lucia Rossetti

AU - Cunha, Fernando Queiroz

PY - 2016/10/4

Y1 - 2016/10/4

N2 - The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.

AB - The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.

U2 - 10.1038/srep34581

DO - 10.1038/srep34581

M3 - Article

C2 - 27698473

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 34581

ER -

Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

Abstract

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