Extracellular Superoxide Dismutase Indirectly Enhances the Release of Immature Neutrophils from the Murine Bone Marrow

Extracellular superoxide dismutase (ecSOD) regulates extracellular concentrations of reactive oxygen species (ROS) to protect tissues during infection and inflammation. Using ecSOD HI, ecSOD WT, and ecSOD KO mice, we have previously shown that ecSOD activity enhances neutrophil recruitment to the liver, yet inhibits the innate immune response against Listeria monocytogenes leading to increased host susceptibility. Using adoptive transfer experiments, we observed that ecSOD activity does not affect neutrophil recruitment or function in a cell-intrinsic manner. Additionally, we noted that ecSOD activity results in decreased retention of immature neutrophils in the bone marrow without altering granulopoiesis. Furthermore, we determined that ecSOD activity protects the extracellular matrix (ECM) and increases concentrations of neutrophil-attracting chemokines leading to an increase in immature neutrophils in the liver. Since ecSOD can be produced by cells from the hematopoietic lineage as well as non-hematopoietic cells, we used bone marrow chimeric mice to investigate the relative contribution of ecSOD produced by cells from each lineage. Ultimately, it was determined that ecSOD from both hematopoietic and non-hematopoietic cells contributes to the overall phenotype observed in ecSOD congenic mice. Collectively, our data suggest that ecSOD activity inhibits degradation of the ECM and promotes egress of immature neutrophils out of the bone marrow and into the liver where they provide inadequate protection against L. monocytogenes. These studies highlight the potential therapeutic value of ecSOD inhibitors to enhance immune responses during bacterial infections.