Immunometabolic & Mitochondrial Regulation of Epigenetics in Lupus

Lupus is a disease where the immune system mistakenly attacks the body’s own tissues and affects each person differently. That makes it hard to treat, since treatments do not work the same way for everyone. One known driver of lupus is the interferon pathway, which normally helps fight viruses. In lupus, this pathway can be switched on even when there is no infection, fueling inflammation and damage. A drug called anifrolumab was designed to block this pathway, but only some patients respond to it, and researchers do not yet understand why. Recent studies suggest that monocytes, a type of immune cell, may hold important clues.

In patients with active lupus, these monocytes show higher interferon activity, putting their mitochondria – the tiny energy-producing “power plants” inside cells – under stress. Stressed mitochondria then send out false alarm signals that can themselves trigger interferon production, creating a vicious cycle. In addition, the DNA that encodes and controls interferon‑related genes may remain continuously “open” in these patients, making expression of those genes easier than it should be. This may also help explain why lupus affects women more often than men, as normally in women, silencing or inactivation of one of the two X chromosomes is required to produce a controlled immune response. In lupus, that silencing breaks down, causing changes in immune‑related genes on the X chromosome, leading to worse inflammation. Changes in mitochondrial function may contribute to this. With experts in lupus, interferon activity, mitochondria, and X chromosome inactivation, Dr. Jefferies and her team will study how these pieces fit together. By analyzing monocytes from the same patients across multiple projects, the team hopes to learn how changes in mitochondrial proteins, metabolites, and mitochondrial stress signals affect DNA regulation, X chromosome gene silencing, the interferon response, and inflammation.

What this means for people with lupus:

The insights gained will help explain why patients differ so much in their responses to treatment, with the goal of identifying biomarkers to group patients and informing the development of personalized therapies.

Although SLE is a complex, heterogeneous disease, increased expression of type I interferon (IFN) and IFN-stimulated genes (ISGs) are the most common immunologic abnormalities. The ISG-signature in SLE is highly variable among patients, but what causes this or whether it underlies differential responsiveness to IFN-targeted therapy is unclear. We have found that mitochondrial deregulation and chromatin remodeling not only lead to SLE-specific phenotypes in monocytes but may also contribute to response to therapy in ISG-high vs ISG-low patients. The proposed program will compare mitochondrial function, chromatin accessibility (including X chromosome inactivation (XCI)) with ISG status and responsiveness to IFN-targeted therapy (anti-IFNAR, anifrolumab). The three projects outlined will use the same monocytes from SLE patients stratified as ISG-high, ISG-low, on anti-IFNAR therapy, and healthy controls (n=10 each group) to extensively characterize mitochondrial function, histone modification, chromatin accessibility and XCI status.

PROJECT 1 (Jefferies, CSMC) – Investigate how mitochondrial and chromatin dynamics change with ISG levels or anti-IFNAR targeting in SLE monocytes. We hypothesize that changes in the mitochondrial proteome and chromatin accessibility will be distinct depending on ISG status. To address this, we will ask: A. What mitochondrial proteomic and metabolomic changes distinguish our 4 subject groups? B. Do changes in histone modifications and altered chromatin accessibility distinguish the 4 groups? PROJECT 2 (Anguera, UPENN) – Investigate whether altered X-Chromosome Inactivation corresponds with ISG status or anti-IFNAR responsiveness in SLE patient monocytes. We will address how X-linked contributions and escape from XCI contribute to ISG status by asking: A. What is the relationship between ISG status or anti-IFNAR responsiveness and the epigenetic integrity on the inactive X chromosome (Xi) in SLE monocytes? B. Does gene expression from the Xi in SLE monocytes contribute to ISG status or anti-IFNAR responsiveness? PROJECT 3 (Shadel, Salk Institute) – Mitochondrial dysfunction and nucleic acid release in SLE monocytes. We will characterize how disrupted mitochondrial homeostasis in monocytes and macrophages contribute to patient ISG status and anti-IFNAR responsiveness. We will: A. Fully characterize mitochondrial morphology, function, dynamics, mitophagy and signaling pathways associated with mitochondrial stress and homeostasis in the 4 subject groups. B. Determine the type, degree, and mechanism of mitochondrial nucleic acid release in SLE monocytes with different basal ISG states.

Analyzing this data based on ISG status or anti-IFNAR responsiveness, we predict will provide unprecedented insight into the heterogeneity of SLE disease, illuminate new pathways that can be targeted to improve anti-IFN targeted therapies, and identify biomarkers that predict response to anti-IFNAR treatment.