Modulation of respiratory syncytial virus-induced epithelial proinflammatory mediator HMGB1 via activation of histone deacetylase

Abstract

Abstract Respiratory syncytial virus (RSV) is the leading cause of serious respiratory illness in children and a major cause of severe respiratory morbidity and mortality in the elderly, for which no effective treatment or vaccine is currently available. High Mobility Group Box-1 (HMGB1) is a redox-sensitive multifunctional nuclear protein that translocates to the cytoplasm and subsequently released to the extracellular space during infection and injury, and regulates immune and inflammatory responses as a damage-associated molecular pattern. Our studies show that RSV-induced oxidative stress hyperacetylates, phosphorylates and oxidizes HMGB1 to promote its extracellular release and that secreted HMGB1 triggers inflammatory responses by activating innate immune cells to promote inflammation. The goal of this study was to investigate the effect of histone deacetylases HDAC1 and sirtuin 1 (SIRT1) activation on RSV-induced epithelial HMGB1 extracellular release and its proinflammatory function. Studies were conducted in airway epithelial cells, a human lung carcinoma cell line and normal small alveolar epithelial cells. Cells were transfected with HDAC1 and SIRT1 siRNA followed by infection with RSV and determined HMGB1 levels by Western blot, ELISA and RT-PCR. Our studies demonstrated that inhibition of deacetylase activity enhanced RSV-induced HMGB1 secretion due to increased acetylation of HMGB1, which promotes inflammation. Activation of deacetylases using resveratrol significantly inhibited RSV-induced HMGB1 release. These studies will lead to the modulation of the RSV-induced epithelial HMGB1 proinflammatory function, which may pave the way for the development of novel therapeutic interventions for RSV infections.