A recent study revealed that mitochondria induce inflammation in lupus through the release of reactive oxygen species into neutrophil extracellular traps (NETs). The research, “Neutrophil extracellular traps enriched in oxidized mitochondria DNA are interferogenic and contribute to lupus-like disease,” offers hope for new lupus treatments.
Neutrophils are white blood cells entrusted with the task of finding and killing pathogens, foreign cells, or clearing cell debris. One of the methods these cells employ is the creation of a web in which bacteria or other infiltrating pathogens get ensnared — NETs.
While NETs can be life saving when neutrophils target pathogens, excessive NET formation can be damaging to tissue and cause cells to die in a process called NETosis. Earlier studies indicate that NETs contribute to lupus pathology, and drugs that inhibit NET formation improve lupus symptoms in mouse models of the disease.
But researchers are still in the dark regarding how NETs are generated and how they cause inflammation in diseases without an infectious component, such as lupus.
In the study, which appeared in the journal Nature Medicine, the team observed that formation of the RNA-protein immune complexes found in lupus tissue induces NETosis via mitochondrial reactive oxygen species. When such immune complexes trigger neutrophils to produce NETs, the mitochondria migrate to the cell surface and release oxidized mitochondrial DNA through the NET. The presence of the oxidized DNA outside the cell triggers an inflammatory reaction.
When researchers — under the lead of University of Washington Professor Keith B. Elkon and Mariana J. Kaplan, of the National Institutes of Health — injected such oxidized DNA into mice, DNA sensors detected its presence and activated a protein named STING, which, in turn, sent a warning signal. This caused the release of type 1 interferons, triggering an immune response.
Researchers then treated a lupus mouse model with scavengers that clear reactive oxygen species, noticing that the interferon signaling, as well as the degree of lupus symptoms, were reduced. The study also explored these mechanisms in isolated neutrophils from lupus patients, as well as in cells from patients with chronic granulomatous disease. The researchers observed that NETs released from these cells contained high levels of oxidized mitochondrial DNA, and that reactive oxygen species mediated cell death through NETosis in human cells.
The results stress the importance of mitochondrial reactive oxygen species in NET formation and autoimmune pathology. According to the authors, the results are a timely contribution to research on autoimmune diseases since reactive oxygen species (ROS) inhibitors are in clinical trials for other diseases. This enables the study of such inhibitors in diseases like lupus, and offers hope of new treatment approaches.