Nox NADPH oxidases are major sources of signaling oxidants in a variety of cell types, while in phagocytes Nox2 is essential for microbial killing and host defense. Genetic mutations impairing the Nox2 complex in humans associate with chronic granulomatous disease, a severe immunodeficiency that courses, however, with a paradoxical proinflammatory state. Recent work involving a cooperation between 2 CEPIDs, the Center for Research in Inflammatory Diseases (Fernando Q. Cunha) and Redoxoma (Lucia R Lopes) helped shedding light onto this complex phenomenon . The investigators showed that during Nox2 activation, there is a parallel pathway that prevents the nuclear migration of thioredoxin-1 (Trx1), a major dithiol reducing system in cells. Nuclear migration of Trx-1 sustains the thiol reduction-dependent DNA binding of the transcription factor NF-κB, well known to mediate the transcription of several proinflammatory genes. By restricting Trx1 migration, Nox2 plays a paradoxical antiinflammatory role, while exerting its oxidative killing of microbes. The mechanism of Nox2 effects on Trx1 involves the p40phox subunit, a somewhat obscure component of the Nox2 complex, which binds Trx1 at the cytosol and prevents its migration to the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin impair this pathway and promote nuclear accumulation of Trx1 after bacterial lipopolysaccharide cell stimulation, leading to enhanced transcription of inflammatory mediators through NF-κB. Such NF-κB overactivation is prevented by keeping Trx1 in the oxidized state through the use of inhibitors of thioredoxin reductase-1 (TrxR-1, the enzyme that normally reduces Trx1 at the expense of reducing equivalents from NADPH). The investigators further investigated whether the Nox2/Trx1/ NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (i.e., impaired Nox2) and sepsis. The results showed that TrxR-1 inhibition prevents nuclear accumulation of Trx1 as well as bacterial lipopolysaccharide-stimulated overproduction of the proinflammatory mediator tumor-necrosis-factor-α by monocytes and neutrophils from patients with chronic granulomatous disease. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin, also increase survival rates of mice undergoing sepsis in the model of cecal-ligation-and-puncture. Therefore, these results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to understand the pathophysiology of hyperinflammation in chronic granulomatous disease and sepsis. In addition, these data raise the possibility that TrxR-1 inhibitors could be novel adjuvants in the treatment of sepsis, particularly in patients with infections associated with chronic granulomatous disease.
- S. C. Trevelin, C. X. dos Santos, R. G. Ferreira, L. de Sá Lima, R. L. Silva, C. Scavone, R. Curi, J. C. Alves-Filho, T. M. Cunha, P. Roxo-Júnior, M. C. Cervi, F. R. Laurindo, J. S. Hothersall, A. M. Cobb, M. Zhang, A. Ivetic, A. M. Shah, L. R. Lopes, F. Q. Cunha.
Apocynin and Nox2 regulate NF–κB by modifying thioredoxin-1 redox-state.
Scientific Reports, 6: 34581, 2016 | doi: 10.1038/srep34581