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

Abstract

Respiratory virus infections are invariably accompanied by an increase in oxidative stress, characterised by elevated production of Reactive Oxygen Species (ROS) in the lung, which plays a pivotal role in both pathogenesis and host defence. Using a mouse model, neutrophil NADPH Oxidase 2 (Nox2) emerges as a key player, primarily responsible for generation of ROS during the early phases of Influenza A Virus (IAV) infection. Neutrophil Nox2-derived ROS display a multifaceted role, not only unleashing oxidative stress but in turn curbing Neutrophil-derived IL-1beta signalling. Absence of neutrophil Nox2 triggered heightened production of IL-1β, promoting the proliferation of IL-17-producing gamma delta (gamma delta) T cells. This early self-amplified augmentation of the IL-beta/IL-17 axis counteracted the antiviral interferon response against IAV infection in mice. We extended our findings to humans. Similar patterns of ROS production and cytokine regulation were observed in human neutrophils when exposed to virus analogue poly(I:C) and SARS-CoV-2. 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.