Oxidized mitochondrial DNA employs APEX1 in neutrophils to control lupus

The immune system keeps watch for viral DNA that signals we have an infection. In lupus, immune cells identify DNA from patients’ cells as dangerous. Some of the DNA released by their cells comes from mitochondria, the structures that provide energy for our cells. Dr. Zhang has identified several proteins that may recognize this DNA, including one known as APEX1. In his new study, he will test whether APEX1 detects mitochondrial DNA and spurs the immune system attacks. His results could provide important information for the development of safer and more effective approaches for the prevention and control of lupus without unwanted side effects.

What this study means to people with lupus

The immune system mistakenly attacks lupus patients’ own DNA. Dr. Zhang’s study is testing whether the protein he just discovered, APEX1, is responsible for sounding a distress call that stimulates our defensive cells — an impressive discovery that would allow researchers to develop new ways to prevent this false alarm.

This proposal is designed to uncover key molecular sensors in lupus and how such sensors might mediate in the disease process. In lupus patients, the innate immune system reacts to the body’s own nucleic acids and ribonucleoproteins as foreign antigens, which activate B cells to produce antibodies against self-constituents. These autoantibodies present in lupus patients activate neutrophils to release neutrophil extracellular traps (NETs). NETs contain oxidized (Ox) mitochondrial DNA (mtDNA), and are critically involved in the disease process. Whether this Ox mtDNA stimulates cytosolic sensors in a cell-autonomous manner is not clear. Strikingly, besides forming NETs, the lupus neutrophil itself shows high type I interferon (IFN-I) signatures and proinflammatory cytokines; and Ox mtDNA is massively accumulated in pediatric lupus neutrophils, supporting the notion that cytosolic Ox mtDNA contributes to lupus. In our pilot experiments we screened a plethora of DNA-binding proteins in immune cells and identified several novel DNA sensors. Among them, the apurinic/apyrimidinic endonuclease 1, also known as APEX1, is required to produce IFN-I and proinflammatory cytokines in lupus neutrophils; knockout of APEX1 abolishes cytokines production in response to cytosolic Ox mtDNA in neutrophils. We hypothesize that APEX1 is a novel Ox mtDNA sensor that triggers autoimmunity in lupus.