Excessive Reactive Oxygen Species Inhibit IL-17A+ γδ T Cells and Innate Cellular Responses to Bacterial Lung Infection

Abstract

Aims: Excessive reactive oxygen species (ROS) are detrimental to immune cellular functions that control pathogenic microbes; however, the mechanisms are poorly understood. Our aim was to determine the immunological consequences of increased ROS levels during acute bacterial infection. Results: We used a model of Streptococcus pneumoniae (Spn) lung infection and superoxide dismutase 3-deficient (SOD3^-/-) mice, as SOD3 is a major antioxidant enzyme that catalyses the dismutation of superoxide radicals. First, we observed that in vitro, macrophages from SOD3^-/- mice generated excessive phagosomal ROS during acute bacterial infection. In vivo, there was a significant reduction in infiltrating neutrophils in the bronchoalveolar lavage fluid and reduced peribronchial and alveoli inflammation in SOD3^-/- mice 2 days after Spn infection. Annexin V/propidium iodide staining revealed enhanced apoptosis in neutrophils from Spn-infected SOD3^-/- mice. In addition, SOD3^-/- mice showed an altered macrophage phenotypic profile, with markedly diminished recruitment of monocytes (CD11c^lo, CD11b^hi) in the airways. Further investigation revealed significantly lower levels of the monocyte chemokine CCL-2, and cytokines IL-23, IL-1β, and IL-17A in Spn-infected SOD3^-/- mice. There were also significantly fewer IL-17A-expressing gamma-delta T cells (γδ T cells) in the lungs of Spn-infected SOD3^-/- mice. Innovation: Our data demonstrate that SOD3 deficiency leads to an accumulation of phagosomal ROS levels that initiate early neutrophil apoptosis during pneumococcal infection. Consequent to these events, there was a failure to initiate innate γδ T cell responses. Conclusion: These studies offer new cellular and mechanistic insights into how excessive ROS can regulate innate immune responses to bacterial infection.

Keywords: ROS; SOD3; Streptococcus pneumoniae; innate immunity; interleukin-17; γδ T cells.