Divergent Roles of Extracellular Superoxide Dismutase During Intracellular Bacterial Infection

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Alexandra Witter; Witter, Alexandra R; Break, Timothy J; Okunnu, Busola M; Swanta, Naomi; Berg, Rance E, PhD
Cell Biology and Anatomy
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Extracellular superoxide dismutase (ecSOD) regulates extracellular concentrations of reactive oxygen species (ROS) to protect tissues during infection and inflammation. Using congenic mice with varying levels of ecSOD activity (ecSOD HI, WT and KO), we have previously shown that ecSOD activity enhances neutrophil recruitment to the liver, yet inhibits the innate immune response against Listeria monocytogenes (LM) leading to increased host susceptibility. Additionally, we determined that ecSOD activity protects the extracellular matrix (ECM) from degradation and promotes egress of immature neutrophils out of the bone marrow and into the liver where they are unable to provide protection against LM. Since ecSOD can be produced by cells from the hematopoietic lineage as well as somatic cells, the potential contribution of ecSOD produced by cells from each lineage required further investigation.In order to determine the relative contributions of ecSOD produced from either hematopoietic-derived cells or somatic cells, we generated bone marrow chimera mice using ecSOD KO mice and C57Bl/6 mice. Briefly, host mice were irradiated to eliminate hematopoietic lineage cells and reconstituted with bone marrow cells isolated from donor mice. Control groups consisted of ecSOD KO mice reconstituted with bone marrow from ecSOD KO donors (KO -> KO) or C57Bl/6 mice with bone marrow from C57Bl/6 mice (WT -> WT). Experimental groups consisted of ecSOD KO mice reconstituted with bone marrow from C57Bl/6 mice (WT -> KO) or C57Bl/6 mice with bone marrow from ecSOD KO mice (KO -> WT). All mice were then infected with LM and evaluated for neutrophil recruitment and bacterial burden.We observed that ecSOD produced by hematopoietic cells leads to increased bacterial burden during LM infection, while ecSOD produced from somatic cells is essential for increased neutrophil recruitment. Collectively, our data suggest that ecSOD produced by both hematopoietic cells and somatic cells is involved in our observed phenomena; however, the contribution of ecSOD from each cell lineage is skewed towards either increased neutrophil recruitment or increased susceptibility to LM infection, but not both. These studies highlight the potential therapeutic value of ecSOD inhibitors to enhance immune responses during bacterial infections.