Respiratory Syncytial Virus–Induced Activation of Nuclear Factor–κB in the Lung Involves Alveolar Macrophages and Toll-Like Receptor 4–Dependent Pathways

The transcription factor nuclear factor (NF)–κB controls the expression of numerous respiratory syncytial virus (RSV)–inducible inflammatory and immunomodulatory genes. Using a BALB/c mouse model, the present article shows that RSV potently and specifically activates NF-κB in vivo, a process that involves nuclear translocation of the subunits RelA, p50, and c-Rel in the lung. By depletion of alveolar macrophages (AMs) in BALB/c mice and use of C3H/HeJ mice lacking a functional Toll-like receptor (TLR)–4 signaling pathway, we demonstrate the existence of distinct but sequentially integrated RSV-inducible early NF-κB responses in the lung. The first response occurs early after RSV inoculation, is AM and TLR4 dependent, and is viral replication independent, whereas the second response involves epithelial cells and/or inflammatory cells, is TLR4 independent, and requires viral replication. NF-κB may be considered a central activator of not only inflammatory but also innate immune responses to RSV