Neutrophil NADPH oxidase breaks the inflammatory IL-1β/IL-17A circuit to enhance pathogen clearance during respiratory virus infections.

Abstract

Respiratory virus infections are invariably accompanied by an increase in oxidative stress through elevated production of Reactive Oxygen Species (ROS), which contribute to both host defence and pathogenesis. Using mouse models, we identify neutrophil NADPH Oxidase 2 (Nox2) as the major early source of ROS during Influenza A Virus (IAV) infection. Surprisingly, neutrophil Nox2-derived ROS display multifaceted effects, not only unleashing oxidative stress but also limiting pro-inflammatory IL-1β signalling. Absence of neutrophil Nox2 enhances IL-1β production, promoting the proliferation of IL-17-producing gamma delta (γδ) T cells. This early self-amplified augmentation of the IL-1β/IL-17 axis is associated with increased viral burden and reduced IFNα expression in the lung. We extend our findings to humans. Similar patterns of ROS production and cytokine regulation are observed in human neutrophils when exposed to IAV and the viral RNA analogue poly(I:C). Our discovery highlights that ROS, often associated with harm, play a dual role by regulating cytokine signalling and thus influencing the immune response against respiratory viruses.