Researchers at Linköping University have identified in mice the cells within the blood vessels of the brain which are essential for a fever response. The outcomes have been published in PNAS, and answer a long-standing query of which organs are involved in producing fever.

Everyone gets fevers, occasionally. If we understand the mechanisms behind fever, we also can understand how latest drugs and coverings can work.”

Anders Blomqvist, Professor Emeritus, Department of Biomedical and Clinical Sciences, Linköping University

Fever is the body’s response to infection or inflammation, and a defence mechanism against, for instance, viruses and bacteria. When affected by infection or inflammation, the body releases molecules often called cytokines into the blood circulation. These molecules are too large to go through the blood-brain barrier, a network of tiny blood vessels that protects the brain from harmful substances. But fever is only a symptom, which becomes manifest after the brain has itself released signals. So how does the brain detect that the body is affected by an inflammation or infection?

The reason will be present in receptors situated on the outer surface of the blood-brain barrier that detect the cytokines. These receptors pass the signal on to cells on the inner surface of the blood-vessel partitions within the blood-brain barrier, often called endothelial cells. They then start to provide the hormone-like molecule prostaglandin E2, which in turn prompts receptors within the hypothalamus, which acts because the body’s thermostat. A fever response has been initiated. It has, nevertheless, been unclear until now whether that is the one mechanism behind fever.

It has previously been believed that prostaglandin should be produced also in certain cells of such organs because the liver and lungs with a view to start a fever response. However the researchers at Linköping University have now shown that this is just not the case. In a study on mice published in Proceedings of the National Academy of Sciences, PNAS, Anders Blomqvist and his colleagues show that the endothelial cells of the brain are the one ones required for a fever response to be produced.

“Our results answer a matter that has been asked for several many years. There has not previously been any evidence that only the endothelial cells within the brain are needed to begin a fever response. We’ve got now filled this gap in our knowledge,” says Anders Blomqvist.

The researchers have worked with gene-modified mice during which they’ve removed certain genes that code for prostaglandin production within the brain endothelial cells. The mice were subsequently injected with substances which are present within the cell partitions of certain bacteria, producing in this manner fever. The gene-modified mice didn’t show any fever response after the injection.

This allowed the researchers to conclude that these endothelial cells are essential to elicit fever, but didn’t show whether or not they are sufficient. For that reason, the researchers conducted tests on one other gene-modified mouse model during which the one cells that would produce prostaglandin E2 were the brain endothelial cells. These mice exhibited a fever response, which confirms that the brain endothelial cells are, indeed, sufficient.

These experiments have been made possible using advanced techniques for managing and examining experimental animals. By surgically inserting an intravenous catheter and recording body temperature using telemetry, each the injections and the measurements will be made without causing stress for the animal, which suggests that the fever response will be observed more accurately.

“Most of the people has long believed that the body temperature of small animals is higher than that of humans and other large mammals, around 40 degrees. However the measurements have been erroneous, for the reason that animals became stressed in the course of the process. The techniques we now have used show that the mice have the identical temperature as humans,” says Anders Blomqvist.

The research has received financial support from the Swedish Research Council, the Swedish Brain Foundation and the Swedish Cancer Society.

Source:

Journal reference:

Shionoya, K., et al. (2022) Prostaglandin production selectively in brain endothelial cells is each essential and sufficient for eliciting fever. PNAS. doi.org/10.1073/pnas.2122562119.