Mitochondria, caspases and type I interferons in autoimmunity
The immune system molecules known as interferons protect us from infections, but they also spur tissue damage in lupus. Dr. Rongvaux has discovered a previously unknown mechanism by which interferons may cause or worsen lupus. Using state-of-the-art technologies, he is investigating how some proteins, known as caspases, block this novel interferon mechanism. He also will test molecules that stimulate caspases, some of which are under development as potential treatments for diseases such as cancer, to determine if they reverse lupus symptoms in mice.
What this study means to people with lupus
Dr. Rongvaux is using state-of-the-art technology to study a newly discovered process that may cause or worsen lupus. His group is trying to find out whether molecules involved in this process are potential targets to validate and advance new treatments, that may reverse symptoms of lupus.
Type I interferons (IFNs) play a critical role in several autoimmune diseases, such as systemic lupus erythematosus (SLE). We recently discovered a previously unknown mechanism of type I IFN regulation. This complex mechanism involves the antagonistic actions of cytosolic mitochondrial DNA (mtDNA) and pro-apoptotic caspases, which together control the activation of the intracellular DNA-sensing pathway, cGAS/STING. In this project, we propose to study the role of mitochondria and caspases in the initiation and progression of autoimmunity, using novel mouse models and other state-of-the-art technologies. Specifically, we will first demonstrate the functional capacity of mtDNA and caspase-dependent type I IFNs to induce autoimmune symptoms. Next, we will determine the experimental and pathological conditions that could result in cGAS/STING induction by cytosolic mtDNA. Finally, we will investigate the mechanism by which caspases silence this IFN response, and how it could be exploited therapeutically. Since pharmacological modulators of mitochondrial permeability and of caspase activity are available, our work on this fundamental mechanism of regulation of the IFN response has the potential to validate a novel target and advance new therapeutic approaches to treat SLE and other autoimmune diseases.