Fumarate hydratase helps to control macrophages that drive inflammation
Marisa Wexler, MS
An enzyme called fumarate hydratase is involved in the control of the inflammatory activity of macrophages, a type of immune cell with a central role in driving inflammatory disorders like lupus, researchers report.
“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,” Luke O’Neill, PhD, a professor of biochemistry at Trinity College Dublin and the study’s senior author, said in a university press release.
The study, “Macrophage fumarate hydratase restrains mtRNA-mediated interferon production,” was published in the journal Nature.
Potential for fumarate hydratase enzyme to be lupus treatment target
Macrophages are immune cells with critical roles in inflammation. While vital to defending the body against infectious agents, they also are involved in autoimmune diseases characterized by runaway inflammation, like lupus.
These immune cells have several tasks. One is to release inflammatory signaling molecules called cytokines that help to coordinate immune responses. Excess production of a particular cytokine called interferon-beta has been strongly implicated in the immune dysregulation that drives lupus.
Fumarate hydratase is an enzyme known to play roles in cellular metabolism, how cells make and use energy.
Researchers found that blocking the activity of this enzyme in macrophages led to an increase in the cells’ production of interferon-beta.
They also found that macrophages from lupus patients have abnormally low levels of fumarate hydratase. These findings suggest that dysregulation of this enzyme may be a factor that drives lupus, and they imply that fumarate hydratase could be a potential target to treat the disorder.
“We … identify a protective role for [fumarate hydratase] in maintaining appropriate macrophage cytokine and interferon response,” the scientists wrote.
In a battery of cellular experiments, researchers showed that reduced fumarate hydratase activity leads to increased interferon production through a process that is dependent on mitochondria. These small cellular structures are key for energy generation, but they have other important functions.
“Although mitochondria are often referred to as the powerhouses of the cell, these organelles can also act as signaling hubs that control physiological processes,” a pair of scientists at Northwestern University wrote in an accompanying editorial article. This new study’s findings “expand our understanding of how the mitochondria mediate immune responses,” they added.
Most of a cell’s genetic information is stored in the form of DNA inside a cell’s nucleus. But mitochondria also have their own DNA, called mitochondrial DNA or mtDNA. Like genes in the nucleus, genes in mitochondrial DNA are transcribed into an intermediary molecule called RNA, which is then used as a template to make proteins.
Researchers demonstrated that blocking fumarate hydratase caused RNA to be released from mitochondria. These RNA molecules activated the RNA sensors MDA5 and TLR7 to ultimately stimulate the production of pro-inflammatory interferon-beta.
“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,” said Christian Peace, a study co-author and researcher at Trinity.
Further experiments suggested that RNA might be released from mitochondria due to changes in the electrical activity of the mitochondrial membrane, which plays a key role in energy production.
The accompanying editorial noted that a separate study, also published in Nature, suggested that blocking fumarate hydratase led to molecular modifications in certain mitochondrial proteins. These two models could fit together, the scientists noted, since it’s possible that modifications in mitochondrial proteins might lead to altered electrical activity at the membrane. Further research will be needed to test this idea, they added.
A notable limitation of this work, the researchers stressed, is that with current knowledge it’s impossible to say whether decreased fumarate hydratase activity is a cause of lupus or a consequence of disease processes that end up contributing to further inflammation.
Still, findings could serve as a starting point for research in lupus, other autoimmune conditions, and cancers.
“Because the [immune] system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” O’Neill said.
