Repression of Fumarate Hydratase triggers inflammatory pathways in diseases like Lupus and Sepsis, presenting a promising target for new therapies.
What goes wrong in our bodies during the progression of an inflammatory disease? Scientists at the School of Biochemistry and Immunology in the Trinity Biomedical Sciences Institute at Trinity College Dublin have made a significant advancement in comprehending the underlying mechanisms of the progression of inflammatory diseases. The discovery has uncovered a promising new target for therapeutic intervention.
The researchers have discovered that the repression of an enzyme called Fumarate Hydratase occurs in macrophages, which are a type of inflammatory cell that play a role in various diseases such as Lupus, Arthritis, Sepsis, and COVID-19.
Professor Luke O’Neill, Professor of Biochemistry at Trinity is the lead author of the research article that has just been published in the leading international journal, Nature.
He said: “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.”
Mechanisms Linking Fumarate Hydratase and Inflammation
Joint first-author Christian Peace added: “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.”
Fumarate Hydratase was shown to be repressed in a model of sepsis, an often-fatal systemic inflammatory condition that can happen during bacterial and viral infections. Similarly, in blood samples from patients with Lupus, Fumarate Hydratase was dramatically decreased.
“Restoring Fumarate Hydratase in these diseases or targeting MDA5 or TLR7, therefore, presents an exciting prospect for badly needed new anti-inflammatory therapies,” said Prof O’Neill.
Excitingly, this newly published work is accompanied by another publication by a group led by Professor Christian Frezza, now at the University of Cologne, and Dr. Julien Prudent at the MRC Mitochondrial Biology Unit (MBU), who have made similar findings in the context of kidney cancer.
“Because the system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” added Prof O’Neill.
Reference: “Macrophage fumarate hydratase restrains mtRNA-mediated interferon production” by Alexander Hooftman, Christian G. Peace, Dylan G. Ryan, Emily A. Day, Ming Yang, Anne F. McGettrick, Maureen Yin, Erica N. Montano, Lihong Huo, Juliana E. Toller-Kawahisa, Vincent Zecchini, Tristram A. J. Ryan, Alfonso Bolado-Carrancio, Alva M. Casey, Hiran A. Prag, Ana S. H. Costa, Gabriela De Los Santos, Mariko Ishimori, Daniel J. Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Von Kriegsheim, Michael P. Murphy, Caroline Jefferies, Christian Frezza and Luke A. J. O’Neill, 8 March 2023, Nature.
DOI: 10.1038/s41586-023-05720-6
The Trinity study is a collaboration between eight universities including the MRC MBU, University of Cambridge where Dr. Dylan Ryan is co-first author along with Dr. Alex Hooftman, who is now based at the Swiss Federal Institute of Technology Lausanne. Cedars Sinai Medical Centre in Los Angeles is another key collaborator helping with the study of Lupus patients.
The study was funded by the European Research Council, Medical Research Council, and Science Foundation Ireland. Work in the Frezza lab is also supported by the ERC, further illustrating the importance of ERC funding for EU science.
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