Reactive oxygen species (ROS) play an important role in cell signaling and homeostasis. They also seem to be critical for the formation of neutrophil extracellular traps (NETs), which typically form in response to pathogens. Unfortunately, although ROS are important for antimicrobial defense, they can be damaging, particularly to DNA. As a result—and not surprisingly, multiple mechanisms are in place to protect the body from the dangerous aspects of ROS, such as ROS-induced damage to genomic DNA. These protective mechanisms are particularly important because NETosis is a unique form of cell death in which genomic DNA and mitochondrial DNA are exposed to ROS. Mitochondrial DNA is especially vulnerable to ROS during NETosis, because it lacks protection from histones. Perhaps to compensate for this vulnerability, mitochondria that are damaged by ROS typically lose their membrane potential and undergo either mitophagy or extrusion. This process prevents the mitochondria from continuing to produce ROS and, therefore, limits damage to healthy tissue.
However, researchers now have reason to believe these safety mechanisms may be disrupted in individuals with inflammatory disease. Evidence is accumulating to suggest that aberrant NETosis and/or impaired NET clearance may underlie the pathogenesis of such autoimmune disorders as systemic lupus erythematosus (SLE). In particular, studies have found that lupus lymphocytes have elevated mitochondrial ROS synthesis. The elevated ROS synthesis appears to be exacerbated by the fact that patients with lupus also have a unique subset of pro-inflammatory neutrophils known as low-density granulocytes (LDGs) that increase NET formation. The LDGs are distinct from the normal-density granulocytes (NDGs) seen in healthy individuals.
