2014 Metabolism, General Immune System Function, Human Lupus Biology
RIG-I Regulation of Interferon Signature in SLE
The Study and What it Means to Patients
We will investigate our novel idea that damaged mitochondria (the parts of the cell that produce energy) promote inflammation in lupus. We will test whether damaged mitochondria leak RNA that could potentially be mistaken for a virus, stimulating the release of interferon, a molecule that is known to contribute to inflammation in lupus. Our research could lead to new treatment approaches to switch off interferon production in lupus and other autoimmune diseases.
Production of type I interferons can be triggered by foreign RNA, the genetic material in some viruses, which has a different structure from human RNA. Our cells detect this difference using specialized receptors. However, the part of the cell that converts nutrients into a form of energy that can power the cell, the mitochondrion, contains RNA molecules that are highly similar to the RNA from viruses. We know that the RNA from human mitochondria can bind to the receptors that normally detect viral RNA, leading to production of type I interferon. We also know that the mitochondria in cells from patients with lupus are damaged, in that the mitochondrial membrane is prone to leak or rupture which can lead to cell death. We plan to test blood cells from patients with lupus to see whether these damaged mitochondria leak their RNA into the cell, which could stimulate production of type I interferon. If correct, drugs that target damaged mitochondria might be useful therapies for lupus.
A signature of lupus is activation of type I interferon (IFN) production in peripheral blood cells. A major route to type I IFN activation is the RNA-sensing family of RIG-I-like Receptor (RLR) helicases, which includes RIG-I and MDA5. These sensors are triggered by uncapped viral RNA, but not by capped mammalian RNA. We have determined that the RLR route is also regulated by caspase-8 and its paralogue, c-FLIP. c-FLIP levels are elevated in the blood cells of patients with lupus. It is notable that mitochondria contain uncapped RNA, and we have shown that this mitochondrial RNA is also able to trigger type I IFN production via RLR. Co-investigator Dr. Andras Perl has demonstrated that the blood cells from patients with lupus manifest mitochondrial hyperpolarization, leading to cell death. We hypothesize that this mitochondrial stress will lead to release of mitochondrial RNA and activation of type I IFN production via RLR. This could explain the striking type I IFN signature found in the peripheral blood of patients with lupus.
The specific aims of this work are to:
1. Determine which mitochondrial RNA sequences from stressed hyperpolarized mitochondria activate type I IFN production via RLR.
2. Determine whether the mitochondrial hyperpolarization seen in lymphocytes from patients with lupus results in release of mitochondrial RNA and reflects their metabolic state.