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 Spninfected 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-1b, and IL-17A in Spninfected SOD3 -/mice. There were also significantly fewer IL-17A-expressing gamma-delta T cells (cd 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 cd T cell responses. Conclusion: These studies offer new cellular and mechanistic insights into how excessive ROS can regulate innate immune responses to bacterial infection. Antioxid. Redox Signal. 32,[943][944][945][946][947][948][949][950][951][952][953][954][955][956]

G‐CSFR antagonism reduces mucosal injury and airways fibrosis in a virus‐dependent model of severe asthma

“…Cells were further stained with an antibody cocktail that contained FITC‐CD45, PE‐Siglec F, APC‐F4/80, eFluor 450‐CD11b, PE/Cy7‐CD11c, PerCp/eFluor710‐Ly6G (all from Life Technologies, USA) and analysed on a BD FACSAria. A strict gating strategy was used to exclude cell debris and cell aggregates and subset macrophage populations as previously described (Abdulnour et al, 2016; Anthony et al, 2020). Briefly, CD11b and CD11c were used to differentiate three distinct lung macrophage populations including resident alveolar macrophages (AM; CD45 + F4/80 + SSc High CD11c High CD11b − ), exudative macrophages (ExMacs; CD45 + SSc High F4/80 + CD11c High CD11b + ) and infiltrating monocytes (monocytes; CD45 + SSc High F4/80 + CD11c Low CD11b + ).…”

Differential metabolic requirement governed by transcription factor c-Maf dictates innate γδT17 effector functionality in mice and humans

“…Further exploring the function of mitochondria, we observed differential levels of mitoROS in γδT17 and γδT1 cells. It has been reported that excessive ROS inhibits lung γδT17 cells ( 47 ). We observed a lower level of mitoROS intrinsically in γδT17 cells, while γδT1 cells have higher levels of mitoROS, which may be related to their antitumor effect.…”

House Dust Mite Aeroallergen Suppresses Leukocyte Phagocytosis and Netosis Initiated by Pneumococcal Lung Infection

“…Consequently, a reduction in the phagocytic capacity could contribute towards bacterial outgrowth in the lower airways and may in part underpin why asthmatics have a heightened risk of developing pneumococcal pneumonia (Jounio et al, 2010;Castro-Rodriguez et al, 2020). Pneumococcal infection in mice results in the robust recruitment of monocytes at day 2 post infection under the direction of the CCL2 chemokine, which enhances the killing of pneumococcus (Winter et al, 2007;Anthony et al, 2020). This recruitment is necessary to replenish local macrophage pools because SPN can induce apoptosis of resident macrophages to enhance pneumococcal killing (Aberdein et al, 2013).…”

“…Pneumococcal infection in mice results in the robust recruitment of monocytes at day 2 post infection under the direction of the CCL2 chemokine, which enhances the killing of pneumococcus ( Winter et al, 2007 ; Anthony et al, 2020 ). This recruitment is necessary to replenish local macrophage pools because SPN can induce apoptosis of resident macrophages to enhance pneumococcal killing ( Aberdein et al, 2013 ).…”