PNAS: Brain cells needed for fever

Researchers at Linkping University have found cells
necessary for a fever response in the blood vessels of the brains of mice.
The findings were published in PNAS and answer the long-standing question of which organs are involved in the production
of fever.

"Everyone has a fever
once in a while.
If we understand the mechanisms behind fever, we can also understand how new drugs and treatments work," said
Anders Blomqvist, professor emeritus in the Department of Biomedical and Clinical Sciences.

Fever is the body's response to infection or inflammation and a defense mechanism
against viruses and bacteria, among other things.
When affected by infection or inflammation, the body releases molecules called cytokines into the bloodstream
.
These molecules are too large to pass through the blood-brain barrier, a network of tiny blood vessels that protect the brain from harmful substances
.
But fever is just a symptom, and it becomes apparent
after the brain itself releases signals.
So, how does the brain detect that the body is affected by inflammation or infection?

This can be explained
in receptors that detect cytokines located on the outer surface of the blood-brain barrier.
These receptors transmit signals to cells located on the inner surface of the blood vessel wall inside the blood-brain barrier, known as endothelial cells
.
They then begin to produce the hormone-like molecule Prostaglandin E2, which in turn activates receptors in the hypothalamus, which acts as the body's thermostat
.
The fever reaction has already begun
.
However, until now it was unclear if this was the only mechanism
behind the fever.

It was previously thought that prostaglandins had to be produced in certain cells in organs such as the liver and lungs to cause a fever response
.
But researchers at Linkping University have now shown otherwise
.
Anders Blomqvist and his colleagues demonstrated that only brain endothelial cells produce a fever response
.

"Our findings answer a question
that has been asked for decades.
There was no previous evidence that only endothelial cells in the brain trigger a fever response
.
We have now filled this knowledge gap"
.

The researchers studied genetically modified mice by removing certain genes
encoding prostaglandin production in brain endothelial cells.
The mice were then injected with substances present in the cell walls of certain bacteria, creating a fever
.
There was no febrile reaction
after injection of transgenic mice.

This led the researchers to conclude that these endothelial cells were necessary to cause the fever, but did not indicate whether they were sufficient
.
So the researchers tested another genetically modified mouse model in which the only cells that produce prostaglandin E2 were brain endothelial cells
.
The mice showed a fever response, which confirmed that brain endothelial cells were indeed plentiful
.

These experiments are made possible
using advanced techniques for managing and examining laboratory animals.
Intravenous catheters are surgically inserted and body temperature is recorded using telemetry, injections and measurements can all be performed without stressing the animal, meaning that the fever response
can be observed more accurately.

"The public has long believed that the body temperature of small animals is higher than that of humans and other large mammals, around 40 degrees
.
But the measurements were wrong because the animals felt stressed
in the process.
The technique we used showed that mice are at the same temperature as humans"
.

The study was financially supported
by the Swedish Research Council, the Swedish Brain Foundation and the Swedish Cancer Society.