NF-κB signaling pathway mediates respiratory syncytial virus-induced HMGB1 release in airway epithelial cells to promote an inflammatory response

Abstract Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in young children, the elderly and immunocompromised individuals. In addition to acute morbidity, RSV infections have been linked to both the development and severity of asthma. No effective treatment or vaccine is currently available for RSV. High mobility group box 1 protein (HMGB1) is a multifunctional protein that serves as both a DNA regulatory protein and an extracellular cytokine signaling molecule that promotes airway inflammation as a damage-associated molecular pattern. Although HMGB1 is implicated in the pathogenesis of many inflammatory diseases, its involvement in RSV-induced lung inflammation is not yet investigated. The goal of this study is to investigate the molecular mechanisms that induce the release of HMGB1 and the involvement of the NF-κB and TLR4 pathway in RSV pathogenesis. Human lung epithelial cells were infected with RSV in the presence or absence of human recombinant HMGB1 and harvested over time to analyze HMGB1, NF-κB and TLR4 expression by Western blot, immunohistochemistry and qRT-PCR. Our studies with airway epithelial cells clearly show that RSV-induces a significant release of HMGB1 from cells as a result of its translocation from the nucleus to the cytoplasm and subsequently to the extracellular space; that secreted HMGB1 triggers immune responses by activating primary human monocytes via NF-κB-TLR4 signaling pathway. Blockage of one of these molecules could represent a novel therapeutic strategy in the treatment not only for RSV infection, but also for other respiratory diseases that affect human population at any age.