How to end the body’s fight mode

Study in Nature decodes how cortisone dampens inflammation

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Berlin, 10 April, 2024

Cortisone preparations are extremely effective in suppressing excessive immune reactions. However, surprisingly little was previously known about how exactly they do this. A research team from Charité – Universitätsmedizin Berlin, the University Hospital Erlangen and the University of Ulm has now shed light on the molecular mechanism of action. As the researchers report in the scientific journal Nature*, cortisone reprogrammes the metabolism of immune cells and thus activates the body’s own inflammatory brake. The findings lay the foundation for the development of anti-inflammatory drugs with fewer side effects.

The body’s own cortisone (cortisol) is actually a stress hormone. The organism releases it in order to be able to perform in important situations. For example, the substance intervenes in the sugar and fat balance and influences blood pressure, respiratory rate and heart rate. In higher doses, it also inhibits the activity of the immune system, which is exploited by medicine: artificially produced cortisone preparations, which dampen inflammation even more than the body’s own original, are administered due to their excellent effectiveness in a wide variety of immunological diseases and are among the most widely used drugs of all.

Cortisone not only affects genes, but also cellular power plants

However, cortisone drugs also have side effects that are related to the other effects of the endogenous hormone, particularly at higher doses and prolonged administration. These include, for example, high blood pressure, osteoporosis, diabetes or an increase in weight. In order to develop anti-inflammatory drugs with fewer side effects, a research group led by Prof Gerhard Krönke, Director of the Medical Clinic specialising in Rheumatology and Clinical Immunology at Charité, has now investigated more closely how exactly cortisone exerts its immunosuppressive effect.

“It was previously known that cortisone activates a number of genes in various body cells,” explains Gerhard Krönke. “However, it primarily mobilises the body’s resources in this way, which does not adequately explain its strong immunosuppressive effect. In our study, we have now been able to show that cortisone not only affects the genes of immune cells, but also their powerhouses, the mitochondria. This effect on cell metabolism is in turn crucial for the anti-inflammatory effect of cortisone.”

Weapon factories become energy producers

For the study, the research team focussed on so-called macrophages, i.e. scavenger cells of the immune system that eliminate intruders such as viruses and bacteria, but can also contribute to the development of inflammatory diseases. They investigated how these immune cells – obtained from mice – reacted to inflammatory stimuli in the laboratory and what effects the additional administration of a cortisone preparation had. The researchers observed that cortisone – in addition to its effect on genes – primarily reversed changes in cell metabolism that had been triggered by the inflammatory stimuli.

“When phagocytes are put into combat mode, in simple terms they convert their cellular power stations into weapons factories: Instead of supplying energy, the power stations produce building material for the fight against invaders,” says Gerhard Krönke, describing the processes. “Cortisone turns the power stations back into energy suppliers and thus ends the fight mode, so to speak. The small molecule itaconate plays a particularly important role in this process.”

Itaconate mediates the anti-inflammatory effect of cortisone

Itaconate is an anti-inflammatory substance that the body produces itself in the power stations of its cells. Scavenger cells produce it as part of their activation process, so that the inflammatory reaction recedes after a certain period of time. A prerequisite for the production of this endogenous immune brake is that sufficient “fuel” is available. This is no longer the case once the cellular power stations have been converted into weapons factories, which is why itaconate production comes to a standstill after a while. In the case of a normal, short-term inflammation, this is good timing because the immune response has been able to rest in the meantime.

“In the case of a long-lasting inflammatory stimulus, the drop in itaconate production is a problem because the immune brake fails even though the immune system is still running at full speed – chronic inflammation develops,” explains Dr Jean-Philippe Auger, scientist at the Medical Clinic 3 – Rheumatology and Immunology at the University Hospital Erlangen and first author of the study. “This is where the cortisone comes in. By reprogramming the mitochondrial function, it stimulates the production of itaconate in the phagocytes so that it can develop its anti-inflammatory effect again.”

Search for new active ingredients

Using animal models for asthma and rheumatoid arthritis, the scientists were able to demonstrate the extent to which the anti-inflammatory effect of cortisone depends on itaconate: In animals that did not have the ability to produce itaconate, cortisone was ineffective. So if itaconate mediates the immunosuppressive effect of cortisone: Couldn’t it be administered directly instead of cortisone?

“Unfortunately, itaconate is not particularly suitable as an anti-inflammatory drug because it is unstable and could cause side effects when administered systemically due to its high reactivity,” says Gerhard Krönke. “We also assume that the processes in humans are somewhat more complex than in mice. We therefore want to find new active substances that reprogramme the power plants of the immune cells just as well as cortisone, but with fewer side effects.”

*Auger JP et al. Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids. Nature 2024 April 10, doi: 10.1038/s41586-024-07282-7

About the study

The study was led by Prof Gerhard Krönke, who initiated the work before moving to Charité in the Medical Clinic 3 – Rheumatology and Immunology at the University Hospital Erlangen at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU). The first author of the publication, Dr Jean-Philippe Auger, continues to work there. Prof Jan Tuckermann from the University of Ulm and Eicke Latz, Professor of Experimental Rheumatology at the Charité and Scientific Director of the German Rheumatism Research Centre Berlin (DRFZ), a Leibniz Institute, also contributed to the study. Gerhard Krönke and Eicke Latz are working together in Berlin to develop new anti-inflammatory drugs and advance personalisation in rheumatology.

Image : A scavenger cell activated by an inflammatory stimulus and treated with cortisone. Cortisone not only affects the genes in the cell nucleus (blue), but also the cell power plants (red) © Charité | Brenda Krishnacoumar