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

作者：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^*

来源：Scientific Reports, 2016, 6(1): 34581.

DOI：10.1038/srep34581

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.

• 出版日期2016-10-4