Early Interleukin-6 Signalling is a Critical Driver of Immune Regulation during Respiratory Syncytial Virus Infection

The inflammatory cytokine IL-6 is known to have diverse roles in both innate and adaptive immunity. In humans severe infection with Respiratory Syncytial Virus (RSV) is characterized by elevated levels of IL-6, however the IL-6 174-C/C haplotype, which favours lower IL-6 production, is associated with increased risk of both RSV and Rhinovirus infections. Intranasal infection of adult BALB/c mice with RSV A2 resulted in increased IL-6 concentrations in the airways, lung and circulation, peaking at 1 day post infection but detectable for at least two weeks post infection. Treatment of RSV infected mice with a neutralizing anti-IL6 antibody, starting at day -1 for two weeks, resulted in significantly increased disease severity compared to controls, corresponding with increased numbers of virus specific CD8⁺ T cells in the airways and lungs. Importantly however it did not affect peak viral load or viral clearance.  Increased disease severity could be recapitulated by neutralizing IL-6 early (days -1 to +3 post RSV) but not late (days +5 to +14 post RSV). Early IL-6 acted through promotion of both local and systemic levels of the immunoregulatory cytokines IL-10 and IL-27. Loss of IL-6 resulted in reduced numbers of IL-27⁺ lung macrophages by 24 hours and IL-10⁺ CD4⁺ T cells by 96 hours post infection; phenotypes that could be recapitulated by using anti IL-6R blocking antibodies.  Overall, we found that while IL-6 is considered a pro-inflammatory cytokine, during RSV infection it plays a key early role in promoting an immune-regulatory response critical in the resolution of inflammation.