New study refutes textbook theory on macrophage metabolism.

Macrophages, also known as scavenger cells, are immune cells which are part of the innate immune system and differentiate from monocytes.  They circulate in the bloodstream and upon differentiation, invade the surrounding tissue and become resident macrophages.  Macrophage activation can result in rather pro-inflammatory responses, serving as host defense mechanisms or in wound healing responses and aiding in tissue repair and remodeling. However, depending on the type of activation, very different subtypes of activation occur.

These activation processes are complex and trigger profound reprogramming of the macrophage metabolism. Detailed research on what exactly takes place in these processes has long been missing.  Now, a study from researchers at the University of Luxembourg has shown that the immune cells behave differently from what was previously assumed in text books. The team state their findings show, for the first time, that the macrophage metabolism upholds the production of antimicrobial substances and fatty acids during activation; in this way, they deliver important resources for the immune responses they trigger.  The opensource study is published in the Journal of Biological Chemistry.

Previous studies show that macrophages differentiate out from monocytes circulating in the blood stream and migrate into the surrounding tissue. Macrophages are activated when they come into contact with cytokines or toll-like receptor agonists, e.g. lipopolysaccharides (LPS). They are then involved in the defence against invading pathogens such as viruses and bacteria. One important actor in macrophage metabolic reprogramming on activation has been shown to be the protein Hif1αα.  It was known that Hif1α is stabilised in activated macrophages despite the presence of oxygen. So it was assumed that the other metabolic pathways were also similar to those in cancer cells.  However, the current study shows that this is not the case, and in macrophages, the introduction of pyruvate into the citric acid cycle is maintained despite the presence of Hif1αα.

The current study shows that LPS-activated macrophages exhibit a metabolic adaptation with overlapping features to hypoxic cells and a unique LPS-specific metabolic signature.  Results show that the most striking difference to hypoxic cells with stabilized HIF1α is that there is no decrease in relative glucose flux through pyruvate dehydrogenase.  Data findings show that the glucose-derived pyruvate is oxidized via pyruvate dehydrogenase to generate citrate in the mitochondria. The lab note that citrate is used for the synthesis of the antimicrobial metabolite itaconate and for lipogenesis, in other words, macrophages allow continued production of itaconic acid, a kind of endogenous antibiotic.

The group state that conversion of pyruvate is a pivotal step in the inflammatory event and presents a starting point for developing anti-inflammatory therapies.  The go on to add that this would be helpful for diseases associated with an excessive inflammatory response, such as allergies or septic shock.  The researchers have proven in experiments that this works in principle, and when they blocked the influence of pyruvate in the citrus cycle the inflammatory responses decreased.

The team surmise that by studying the metabolic reactions involved they have demonstrated a new approach for treating chronic inflammatory diseases.  For the future, the researchers state that they were able to slow down inflammation by pharmacological means which could be a new therapeutic approach for handling allergies or septic shock.

Source: Université du Luxembourg

Macrophage and bacterium.  Credit: Turbosquid.
Macrophage and bacterium. Credit: Turbosquid.

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