Scientists have found that an enzyme called Fumarate Hydratase is repressed in macrophages, a frontline inflammatory cell type implicated in a range of diseases including Lupus, Arthritis, Sepsis and COVID-19.
Professor Luke O’Neill, says:
“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.”
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 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.
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, Luke A. J. O’Neill. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production. Nature, 2023; DOI: 10.1038/s41586-023-05720-6
Trinity College Dublin. “Potential new therapeutic target for inflammatory diseases such as lupus and sepsis.” ScienceDaily. ScienceDaily, 8 March 2023. <www.sciencedaily.com/releases/2023/03/230308112118.htm>.
Photo by National Cancer Institute