Study Identifies Brain Cells Involved in Eliciting Fever

Researchers in Sweden have identified cells in the brain necessary for inducing fever, solving the long-standing biological question as to which organs are involved in producing the key body response to infection and inflammation.

“Everyone gets fevers, occasionally. If we understand the mechanisms behind fever, we can also understand how new drugs and treatments can work,” says Anders Blomqvist, professor emeritus at the Department of Biomedical and Clinical Sciences, Linköping University.

When affected by infection or inflammation, the body releases molecules known as cytokines into blood circulation. These molecules are too large to pass through the blood-brain barrier, a network of tiny blood vessels that protects the brain from harmful substances. So, the question of how the brain detects that the body is affected by an inflammation or infection and triggers a fever has, until now, gone unanswered.

The explanation can be found in receptors located 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 walls in the blood-brain barrier, known as endothelial cells. They then start to produce the hormone-like molecule prostaglandin E2, which in turn activates receptors in the hypothalamus, which acts as the body’s thermostat and initiates fever.

It was previously believed that prostaglandin must be produced in certain cells of such organs as the liver and lungs in order to start a fever reaction. But the researchers at Linköping University have now shown that this is not the case, and that the endothelial cells of the brain are the only ones required for a fever reaction to be produced.

The study genetically modified mice to remove certain genes that code for prostaglandin production in the brain endothelial cells. The mice were subsequently injected with substances that are present in the cell walls of certain bacteria to produce fever. The gene-modified mice did not show any fever reaction after the injection. This allowed the researchers to conclude that these endothelial cells are necessary to elicit fever but did not show whether they are sufficient. For this reason, the researchers conducted tests on another gene-modified mouse model in which the only cells that could produce prostaglandin E2 were the brain endothelial cells.  These mice exhibited a fever reaction, which confirms that the brain endothelial cells are, indeed, sufficient.

“Our results answer a question that has been asked for several decades. There has not previously been any evidence that only the endothelial cells in the brain are needed to start a fever reaction. We have now filled this gap in our knowledge,” says Blomqvist.

The findings were published recently in Proceedings of the National Academy of Sciences.