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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Trevelin, Silvia Cellone ; dos Santos, Celio Xavier ; Ferreira, Raphael Gomes ; Lima, Larissa de Sa ; Silva, Rangel Leal ; Scavone, Cristoforo ; Curi, Rui ; Carlos Alves-Filho, Jose ; Cunha, Thiago Mattar ; Roxo-Junior, Persio ; Cervi, Maria-Celia ; Martins Laurindo, Francisco Rafael ; Hothersall, John Stephen ; Cobb, Andrew M. ; Zhang, Min ; Ivetic, Aleksandar ; Shah, Ajay M. ; Lopes, Lucia Rossetti ; Cunha, Fernando Queiroz
Total Authors: 19
Document type: Journal article
Source: SCIENTIFIC REPORTS; v. 6, OCT 4 2016.
Web of Science Citations: 14
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)-kappa B. The NF-kappa B overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-kappa B 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)-alpha 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-andpuncture-(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. (AU)

FAPESP's process: 11/03293-3 - Role of Nox2 derived products in the pathogenesis of sepsis
Grantee:Silvia Cellone Trevelin
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis
Grantee:Fernando de Queiroz Cunha
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 13/03520-5 - Role of protein disulfide isomerase in NADPH oxidase dependent ROS generation during hypertension development
Grantee:Lucia Rossetti Lopes
Support type: Regular Research Grants
FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 12/24677-7 - The role of Nox2 in endothelial dysfunction and failure of neutrophil migaration to focus of infection in sepsis
Grantee:Silvia Cellone Trevelin
Support type: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 09/54764-6 - Regulation of redox homeostasis and integrated stress response by Protein Disulfide Isomerase (PDI): mechanisms and role in the pathophysiology and therapy of vascular diseases
Grantee:Francisco Rafael Martins Laurindo
Support type: Research Projects - Thematic Grants