BREAKING! Fumarate Hydratase Discovered As An Enzyme That Holds The Key To Treating Inflammatory Diseases Such As Lupus, Arthritis, Sepsis And COVID-19!

Fumarate Hydratase: In an effort to understand the progression of inflammatory diseases, researchers at the Trinity Biomedical Sciences Institute's School of Biochemistry and Immunology in Trinity College Dublin have made a significant breakthrough. This new understanding reveals a potential therapeutic target for a variety of inflammatory conditions.
 


The team found that an enzyme called Fumarate Hydratase is suppressed in macrophages, which are inflammatory cells involved in numerous diseases, including Lupus, Arthritis, Sepsis, and COVID-19. This discovery, led by Professor Luke O'Neill, Professor of Biochemistry at Trinity.
 
Professor O'Neill commented on the novelty of this discovery, saying, "No one has made a link from Fumarate Hydratase to inflammatory macrophages before, and we believe 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, Dr Christian Peace, further explained the connection between Fumarate Hydratase and immune proteins called cytokines that play a role in inflammatory diseases. He revealed that when Fumarate Hydratase is suppressed, RNA is released from mitochondria, which can bind to crucial proteins 'MDA5' and 'TLR7', leading to the release of cytokines and exacerbating inflammation. This process could potentially be targeted therapeutically.
 
In a sepsis model, Fumarate Hydratase was shown to be suppressed, and it was also found to be significantly reduced in blood samples from Lupus patients.
 
"Restoring Fumarate Hydratase in these diseases or targeting MDA5 or TLR7 presents an exciting prospect for much-needed new anti-inflammatory therapies," said Prof O'Neill.
 
The study findings were published in the peer reviewed journal: Nature
https://www.nature.com/articles/s41586-023-05720-6
 
Metabolic changes play a crucial role in macrophages' effector functions, but the underlying mechanisms are not fully understood.
 
In this study, researchers used unbiased metabolomics and stable isotope-assisted tracing to discover that an inflammatory aspartate-argininosuccinate shunt is activated after lipopolysaccharide stimulation. This shunt, supported by increased argininosuccinate synthase (ASS1) expression, leads to higher cytosolic fumarate levels and fumarate-mediated protein succination.
 
By inhibiting the tricarboxylic acid cycle enzyme fumarate hydratase (FH) pharmacologically or through genetic ablation, intracellular fumarate levels are further increased. This process also suppresses mitochondrial respiration and raises mitochondrial membrane potential. RNA sequencing and proteomics analyses reveal strong inflammatory effects resulting from FH inhibition.
 
Interestingly, acute 13px">Fumarate Hydratase inhibition lowers interleukin-10 expression, which in turn causes increased tumor necrosis factor secretion, an effect mirrored by fumarate esters. Furthermore, Fumarate Hydratase inhibition, but not fumarate esters, enhances interferon-β production through mechanisms involving mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I, and MDA5.
 
This effect is also observed when Fumarate Hydratase is suppressed after prolonged lipopolysaccharide stimulation.
 
Additionally, cells from patients with systemic lupus erythematosus exhibit Fumarate Hydratase suppression, suggesting a potential role for this process in human disease. The study thus identifies a protective function for Fumarate Hydratase in maintaining proper macrophage cytokine and interferon responses.
 
Understanding More About Macrophage Fumarate Hydratase-A Key Regulator of Mitochondrial RNA-Mediated Interferon Production
 
Macrophages are essential immune cells that play a critical role in the body's defense against infections and diseases. Fumarate hydratase (FH) is an enzyme involved in the tricarboxylic acid (TCA) cycle that has recently been discovered to have a significant impact on the immune response, specifically in macrophages.

This section explores the role of macrophage fumarate hydratase in controlling mitochondrial RNA (mtRNA)-mediated interferon production, shedding light on its importance in maintaining balanced immune responses.
 
Macrophage Fumarate Hydratase and Its Role in Inflammation
Recent studies have revealed that the metabolic enzyme fumarate hydratase plays a crucial role in the regulation of macrophage-mediated inflammatory responses. When Fumarate Hydratase is suppressed or inhibited, intracellular fumarate levels increase, leading to the suppression of mitochondrial respiration and an increase in mitochondrial membrane potential.
 
In the context of inflammation, Fumarate Hydratase suppression or inhibition has been shown to reduce the expression of the anti-inflammatory cytokine interleukin-10 (IL-10). This reduction leads to increased production of the pro-inflammatory cytokine tumor necrosis factor (TNF), exacerbating inflammation.
 
Fumarate Hydratase, mtRNA, and Interferon Production
Apart from its role in modulating cytokine production, recent findings suggest that Fumarate Hydratase also influences interferon production in macrophages. Fumarate Hydratase inhibition, but not the use of fumarate esters, has been shown to increase interferon-β production through mechanisms involving the release of mitochondrial RNA (mtRNA) and activation of RNA sensors, such as TLR7, RIG-I, and MDA5. This effect is observed endogenously when Fumarate Hydratase is suppressed following prolonged lipopolysaccharide (LPS) stimulation.
 
Clinical Relevance: Systemic Lupus Erythematosus
The importance of understanding the role of macrophage fumarate hydratase in immune responses is further highlighted by its potential involvement in human diseases. For instance, cells from patients with systemic lupus erythematosus (SLE), a chronic autoimmune disease, exhibit Fumarate Hydratase suppression. This finding indicates that the dysregulation of Fumarate Hydratase may contribute to the pathogenesis of SLE and other inflammatory conditions.
 
The discovery of macrophage fumarate hydratase's role in controlling mtRNA-mediated interferon production has significant implications for our understanding of immune responses and inflammation. By maintaining balanced cytokine and interferon production, Fumarate Hydratase serves as a crucial regulator of macrophage function. Further research is needed to explore the potential of targeting Fumarate Hydratase and related pathways for the development of novel anti-inflammatory therapies for conditions such as systemic lupus erythematosus and other immune-mediated diseases including COVID-19.
 
For more about Fumarate Hydratase, keep on logging to Thailand Medical News.