A new way to treat lupus and sepsis?
What negatively affects the human body in inflammatory diseases when the immune system attacks the body’s own tissues, causing inflammation? Searching for an answer, an international team of scientists supported in part by the EU-funded Metabinnate and ONCOFUM projects made an important discovery that sheds light on this process. In doing so, they also identified a potential new therapeutic target. As described in their study published in the journal ‘Nature’, the researchers discovered that an enzyme called fumarate hydratase is repressed in macrophages – white blood cells in the immune system that destroy harmful microorganisms and trigger other immune cells. However, these inflammatory cell types are implicated in diseases ranging from lupus and arthritis to COVID-19 and sepsis.
What this discovery means
The unprecedented discovery of repressed fumarate hydratase could pave the way for new treatments for different inflammatory diseases such as lupus. “No-one has made a link from Fumarate Hydratase to inflammatory macrophages before and we feel that this process might be targetable to treat debilitating diseases like Lupus, which is a nasty autoimmune disease that damages several parts of the body including the skin, kidneys and joints,” remarks study senior author Prof. Luke O’Neill of Metabinnate project coordinator Trinity College Dublin, Ireland, in a news item posted on the university’s website. In the course of their research, not only did the team find fumarate hydratase levels to be significantly low in blood samples from patients with lupus, they also found that the enzyme was repressed in a sepsis model used. Sepsis is a life-threatening systemic inflammatory condition that is triggered by an existing bacterial or viral infection in the body.
An exciting prospect for anti-inflammatory treatment
Joint first author Christian Peace, a PhD student at Trinity College Dublin, adds: “We have made an important link between Fumarate Hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when Fumarate Hydratase is repressed, RNA is released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, thereby worsening inflammation. This process could potentially be targeted therapeutically.” Prof. O’Neill explains that this could happen by “[r]estoring Fumarate Hydratase in these diseases or targeting MDA5 or TLR7,” adding that this “presents an exciting prospect for badly needed new anti-inflammatory therapies.” The Metabinnate (Metabolic crosstalk in the regulation of inflammation) project ends in May 2024, while ONCOFUM (Integrating the tissue-specificity and chronology of hereditary renal cancer predisposition) continues to February 2025. For more information, please see: Metabinnate project ONCOFUM project
Keywords
Metabinnate, ONCOFUM, macrophage, fumarate hydratase, lupus, sepsis, inflammatory disease, cell, enzyme
