Selenoproteome depletion enhances oxidative stress and alters neutrophil functions in Citrobacter rodentium infection leading to gastrointestinal inflammation

Reactive oxygen species (ROS) play a critical role in modulating a range of proinflammatory functions in neutrophils, as well as regulating neutrophil apoptosis and facilitating the resolution of an inflammatory response. Selenoproteins with the 21st amino acid, selenocysteine (Sec), regulate immune mechanisms through the modulation of redox homeostasis aiding in the efficient resolution of inflammation, while their role in neutrophil functions during diseases remains unclear. To study the role of selenoproteins in neutrophils during infection, we challenged the granulocyte-specific tRNA^Sec (Trsp) knockout mice (Trsp^N) with Citrobacter rodentium (C. rodentium), a murine pathogenic bacterium. Reduced bacterial shedding during the disease-clearing phase and increased tissue damage and neutrophil accumulation in the colon of the Trsp^N mice were observed following infection. Trsp^N neutrophils showed increased intracellular ROS accumulation during ex vivo C. rodentium stimulation and upregulated fMLP or Cx3cl1-induced chemotaxis. We also observed delayed neutrophil apoptosis, reduced efferocytosis of Trsp^N neutrophils, and increased abundance of apoptotic cells in the colon of Trsp^N mice. Together, these studies indicate that selenoprotein depletion results in increased neutrophil migration to the gut accompanied by ROS accumulation, while downregulating neutrophil apoptosis and subsequent efferocytosis by macrophages. Such an increase in inflammation followed by impaired resolution culminates in decreased bacterial load but with exacerbated host tissue damage.