Apocynin and Nox2 regulate NF-κB 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

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 6, p. 12-pg., 2016-10-04.

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: 13/03520-5 - Role of protein disulfide isomerase in NADPH oxidase dependent ROS generation during hypertension development
• Grantee: Lucia Rossetti Lopes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• 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 Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/03293-3 - Role of Nox2 derived products in the pathogenesis of sepsis
• Grantee: Silvia Cellone Trevelin
• Support Opportunities: 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 Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: 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 Opportunities: Scholarships abroad - Research Internship - Doctorate