| Full text | |
| Author(s): Show less - |
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: | 11 |
| 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: | 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 |
| 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: | 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: | 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: | 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: | 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: | 13/07937-8 - Redoxome - Redox Processes in Biomedicine |
| Grantee: | Ohara Augusto |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |