Oxidized DNA (green) accumulates in the mitochondria (red) of neutrophils isolated from SLE patients.
Baylor Institute for Immunology Research has discovered the neutrophils of systemic lupus erythematosus (SLE) patients release oxidized DNA from their mitochondria that can stimulate an unwanted immune response. The study suggests that targeting the pathways that lead to the accumulation of this DNA and/or facilitate its removal could be new ways to treat this chronic autoimmune disease.
Though the initial trigger for SLE remains unknown, it is characterized by the generation of autoantibodies that recognize the patient’s own DNA or RNA-protein complexes and the excessive production of type I interferons, signaling proteins that activate the body’s immune response. Virginia Pascual and colleagues at the Baylor Institute previously discovered that SLE patient neutrophils respond to certain autoantibodies by extruding some of their DNA, which subsequently stimulates another type of immune cell, called plasmacytoid dendritic cells, to produce type I interferons.
They now reveal SLE neutrophils accumulate oxidized DNA within their mitochondria and eventually extrude it from the cell to potently stimulate the production of interferons by plasmacytoid dendritic cells. Mitochondria have their own DNA packaged up into nucleoids. The researchers discovered that, to safely rid themselves of oxidized mitochondrial DNA, neutrophils usually disassemble their nucleoids and transfer the oxidized DNA to the cell’s lysosomes for degradation. However, when SLE neutrophils are exposed to certain autoantibodies, nucleoid disassembly is impaired, and the oxidized DNA is retained inside mitochondria before eventually being extruded from the cell to stimulate interferon production. SLE patients also generatedantibodies against the extruded, oxidized mitochondrial DNA, Caielli et al. found.
Oxidized mitochondrial DNA released from neutrophils therefore induces an immune response and may contribute to SLE pathogenesis. “Therapeutic efforts to enhance pathways involved in oxidized mitochondrial DNA degradation should be explored in human SLE, a disease for which only one new drug has been approved in the past 50 years,” says Pascual. http://www.eurekalert.org/pub_releases/2016-04/rup-bsr041316.php
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