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Researchers from UK and Ireland have made a major breakthrough in understanding what goes wrong in our bodies during the development of inflammatory diseases, and a potential new therapeutic target was discovered during the study.
In a new study, researchers from institutions including Trinity College Dublin, Ireland, and the University of Cambridge, UK, have made a major breakthrough in understanding what goes wrong in our bodies during the development of inflammatory diseases, and in A potential new therapeutic target was discovered in the process. The relevant research results were published online in the journal Nature on March 8, 2023. The title of the paper is “Macrophage fumarate hydratase restrains mtRNA-mediated interferon production“.
The authors found that an enzyme called fumarate hydratase was inhibited in macrophages, a form of inflammation associated with a range of diseases including lupus, arthritis, sepsis, and COVID-19.
Co-corresponding author Luke O’Neill, Professor of Biochemistry at Trinity College Dublin, said: “No one had previously linked fumarate hydratase to inflammatory macrophages, and we felt that targeting this process could potentially treat debilitating diseases such as lupus. Lupus is a nasty autoimmune disease that damages multiple parts of the body, including the skin, kidneys, and joints.”
Co-first author Christian Peace of Trinity College Dublin added, “We have established an important link between fumarate hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when fumarate When hydratase is inhibited, RNA is released from the mitochondria of macrophages, which can bind to key proteins ‘MDA5’ and ‘TLR7’, triggering the release of cytokines, thereby exacerbating inflammation. This process has the potential to become A new therapeutic target.”
Fumarate hydratase has been found to be inhibited in models of sepsis, an often fatal systemic inflammation that can occur during bacterial and viral infections. Likewise, fumarate hydratase was dramatically reduced in blood samples from lupus patients. “Therefore, restoring fumarate hydratase or targeting MDA5 or TLR7 in these diseases offers exciting prospects for much-needed new anti-inflammatory therapies,” said Professor O’Neill.
Alexander Hooftman et al. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production. Nature, 2023, doi:10.1038/s41586-023-05720-6.