Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver

Abstract

Listeria monocytogenes is a Gram-positive intracellular pathogen that causes spontaneous abortion in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals. Although L. monocytogenes can usually be effectively treated with antibiotics, there is still around a 25% mortality rate with individuals who develop clinical listeriosis. Neutrophils are innate immune cells required for the clearance of pathogenic organisms, including L. monocytogenes. The diverse roles of neutrophils during both infectious and noninfectious inflammation have recently gained much attention. However, the impact of reactive oxygen species, and the enzymes that control their production, on neutrophil recruitment and function is not well understood. Using congenic mice with varying levels of extracellular superoxide dismutase (ecSOD) activity, we have recently shown that the presence of ecSOD decreases clearance of L. monocytogenes while increasing the recruitment of neutrophils that are not protective in the liver. The data presented here show that ecSOD activity does not lead to a cell-intrinsic increase in neutrophil-homing potential or a decrease in protection against L. monocytogenes. Instead, ecSOD activity enhances the production of neutrophil-attracting factors and protects hyaluronic acid (HA) from damage. Furthermore, neutrophils from the livers of ecSOD-expressing mice have decreased intracellular and surface-bound myeloperoxidase, are less capable of killing phagocytosed L. monocytogenes, and have decreased oxidative burst. Collectively, our data reveal that ecSOD activity modulates neutrophil recruitment and function in a cell-extrinsic fashion, highlighting the importance of the enzyme in protecting tissues from oxidative damage. Listeria monocytogenes is a Gram-positive bacterium that can be found in the soil, fruits, vegetables, meats, and dairy products. Ingestion of L. monocytogenes-contaminated foods can cause spontaneous abortions in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals (1). Surprisingly, clinical listeriosis results in an ϳ25% mortality rate despite the use of antibiotics (1), which makes understanding the immune response against the pathogen important. Furthermore, L. monocytogenes is a widely used model pathogen to study and understand host-pathogen interactions due to its ease of use and manipulation.Neutrophils are short-lived immune cells that differentiate in the bone marrow from the common myeloid progenitor (2). Under normal homeostatic conditions, most neutrophils are retained in the bone marrow until inflammation leads to signaling for their egress. One of the mechanisms by which neutrophils are recruited out of the bone marrow and into tissues is through the increased production of CXCL1 and CXCL2 (3, 4), which are both induced by the interleukin 23 (IL-23)/IL-17 pathway (5, 6). During lipopolysaccharide (LPS)-induced hepatic injury, hyaluronic acid (HA)-CD44 interactions faci...

Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages

“…Agonist stimulation of neutrophils supports the exocytosis of this cellular compartment, increasing the amount of SOD3 in both the extracellular space and, importantly, on the cell surface [ 57 ]. This release is accompanied by a reduced level of superoxide in the extracellular space and hence modulated redox conditions [ 57 , 59 ]. Macrophages can internalize recombinant SOD3 for storage, implicating a sorting step for deviation from the archetypical endosomal traffic to lysosomes [ 60 ].…”