The Role of Mitochondria in Promoting Dysfunctional Neutrophil Extracellular Traps in Systemic Lupus Erythematosus Pathogenesis

Kirtan Patel

Introduction. Systemic Lupus Erythematosis (SLE) is a chronic autoimmune inflammatory disorder in which anti-nuclear antibodies are thought to cause multi-organ damage2,3,7. Studies have found that plasmacytoid dendritic cells (pDC) are at the center of SLE pathogenesis as they are the prime producers of Interferon-1 (IFN-1)1,5,6. It has long been known that pDCs are activated by dysfunctional neutrophil extracellular traps (NET) because the process involves extruded DNA out into the extracellular matrix where it can react with anti-nuclear antibodies, and thus promote SLE pathogenesis3,4. However, the mechanism behind abnormal NETosis has not been explored and could give potential insight into the disease and novel therapeutic treatments. Methods. Blood was isolated from patients with SLE from the NIH. Heparinized blood was layered on Polymorphprep to isolate neutrophils and NETs. NETs were quantified with Sytox Green intensity by plate reader. Reactive Oxygen Species (ROS) were quantified using ROS MitoSOX detection kit. ELISA was performed to quantify oxidized DNA and was visualized with fluorescent microscopy. DNA was immunoprecipitated through supernatant isolation. MRL/lpr mice were used to quantify in-vivo effect of ROS scavengers. Results. Ribonucleoprotein-Immune complex (RNP-IC) mediated NETosis is dependent on mitochondrial ROS3. Furthermore, RNP-IC stimulated mitochondria are shown to become hypopolarized, migrate to the cell surface, and localize with oxidized DNA3. It was subsequently shown that the oxidized DNA is of mitochondrial origin. Another independent study shows that oxidized mtDNA is required to activate plasma-cytoid dendritic cell mediated production of IFN-11. It was shown that mitochondrial ROS scavengers suppress lupus-like disease in vivo in murine models of lupus3. Conclusion. Studies have shown that dysfunctional mitochondria promote dysfunction in NETosis – specifically, the role of ROS in promoting oxidized mtDNA in NETosis. Abnormal NETosis has been shown to induce SLE-like pathogenesis. ROS scavengers were shown to potentially reduce SLE-like pathogenesis in murine models of lupus by reducing organ damage and anti-DNA antibody levels. Although a cure is far from discovery, this novel insight into the mechanism behind SLE pathogenesis may show a novel therapeutic route of treatment.


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