What happens when macrophage immune cells are activated in the course of an inflammation to combat pathogens such as bacteria or viruses? Researchers of the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg pursued this very question. The researchers discovered that the immune cells behave differently from what was previously assumed. Their 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.
By studying the metabolic reactions involved, the researchers have demonstrated a new approach for treating chronic inflammatory diseases. "We were able to slow down inflammation by pharmacological means," explains Karsten Hiller, Head of the "Metabolomics" research group at LCSB. "There could be a new therapeutic approach here, say for handling allergies or septic shock." The Luxembourg scientists' study is published in the Journal of Biological Chemistry
Macrophages -- also known as scavenger cells -- are immune cells and, as such, are part of the innate immune system. They differentiate out from monocytes circulating in the blood stream and migrate into the surrounding tissue. Macrophages are activated when they come into contact with membrane components of bacteria and viruses, or with inflammatory messengers such as cytokines. They are then involved in the defense against the invading pathogen.
These activation processes are complex and trigger profound reprogramming of the macrophage metabolism. Detailed research on what exactly takes place in these processes had long been missing. One important actor in reprogramming is the protein Hif1α. This protein was already known from earlier studies of cancer cells. If the cells exist in an oxygen-poor environment -- say in the middle of a tumor -- then Hif1α is stabilized, in that its degradation is prevented. As a consequence, via a series of regulatory mechanisms, this ultimately causes less pyruvate to be introduced into the citric acid cycle -- a crucial metabolic pathway in many life forms by which they produce energy and building materials for synthesizing a whole host of molecules.
"It was known that Hif1α is stabilized 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," explains Dr. Johannes Meiser from the Metabolomics group at LCSB. "We have now shown that this is not the case: In macrophages, the introduction of pyruvate into the citric acid cycle is maintained despite the presence of Hif1α."
Macrophages thus allow continued production of itaconic acid, a kind of endogenous antibiotic. In an earlier work, researchers working with Prof. Hiller had shown for the first time that itaconic acid is indeed produced in mammals at all. Synthesis of fatty acids that are needed for macrophage growth can also continue in the course of the inflammatory response.
"Conversion of pyruvate is a pivotal step in the inflammatory event, and thus presents a starting point for developing anti-inflammatory therapies," Hiller says. "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: When they blocked the influence of pyruvate in the citrus cycle, the inflammatory responses decreased.
Illustration: Steps of a macrophage ingesting a pathogen: a. Ingestion through phagocytosis, a phagosome is formed; b. The fusion of lysosomes with the phagosome creates a phagolysosome; the pathogen is broken down by enzymes; c. Waste material is expelled or assimilated (the latter not pictured). Wikipedia.
Science Daily (03/17/16)
Abstract (Journal of Biological Chemistry; 2016, 291 (8): 3932.)
Abstract (Proceedings of the National Academy of Sciences; 2013, 110 (19): 7820.)