Scientists at Trinity College Dublin’s School of Biochemistry and Immunology in the Trinity Biomedical Sciences Institute have made an important breakthrough in understanding what goes wrong in our bodies during the progression of inflammatory diseases, uncovering a potential new therapeutic target in the process.
The researchers discovered that an enzyme called Fumarate Hydratase is suppressed in macrophages, a kind of frontline inflammatory cell linked in a variety of disorders such as Lupus, Arthritis, Sepsis, and COVID-19.
Professor Luke O’Neill, Professor of Biochemistry at Trinity, is the principal author of the study, which was just published in the prestigious international magazine Nature. He stated:
“No one has previously linked Fumarate Hydratase to inflammatory macrophages, and we believe that this mechanism may be targeted to treat severe disorders like Lupus, a horrible autoimmune disease that destroys multiple regions of the body including the skin, kidneys, and joints.”
Christian Peace, a co-first author, added:
“We discovered a crucial relationship between Fumarate Hydratase and immunological proteins known as cytokines, which play a role in inflammatory illnesses. We discovered that when Fumarate Hydratase is inhibited, RNA is released from mitochondria, which can bind to critical proteins ‘MDA5’ and ‘TLR7,’ causing the production of cytokines and thereby increasing inflammation. This mechanism has the potential to be therapeutically addressed.”
Fumarate Hydratase was shown to be suppressed in a model of sepsis, a potentially deadly systemic inflammatory illness caused by bacterial and viral infections. Similarly, Fumarate Hydratase was significantly reduced in blood samples from Lupus patients.
“Restoring Fumarate Hydratase in these conditions, or targeting MDA5 or TLR7, provides an interesting opportunity for much needed novel anti-inflammatory therapeutics,” Prof O’Neill added.
This recently published study is accompanied by another paper 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 discovered comparable discoveries in the context of kidney cancer.
“Since the system may fail in some forms of cancer, the reach of any possible therapeutic target might be expanded beyond inflammation,” Prof O’Neill noted.
The Trinity study is a partnership of eight universities, including the MRC MBU at the University of Cambridge, where Dr Dylan Ryan is co-first author with Dr Alex Hooftman, who is currently located at the Swiss Federal Institute of Technology Lausanne. Another important collaborator in the Lupus study is Cedars Sinai Medical Center in Los Angeles.
The European Research Council, Medical Research Council, and Science Foundation Ireland all provided funding for the study. The ERC also funds research in the Frezza lab, demonstrating the relevance of ERC financing for EU science.
Source: Trinity College Dublin
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