This topic is a straightforward gene-environment interactions study. First, the environmental signal is a bacterial or viral infection; the response is the release of cytokines by specific types of immune cells (at the site of the infection). These cytokines then become an endogenous signal that leads to the response of fever. Since the cytokine molecules are too large to cross the blood-brain barrier, they bind to a receptor on blood-vessel endothelial cells located on the brain outer surface; the receptor then transmits a signal to specific fever-producing cells inside the brain.
Using genetically-modified mice that lack specific genes encoding for prostaglandin production in the brain endothelial cells, and then injecting substances present in cell walls of certain bacteria that typically produce a fever reaction — authors found that these genetically-modified mice did not show any fever reaction after that injection.
Authors then used a different genetically-modified mouse model in which the only cells in the body that are able to produce prostaglandin E2 are the brain surface endothelial cells. Injecting substances present in cell walls of certain bacteria that typically produce a fever reaction — the scientists found that these genetically-modified mice now DID exhibit a normal fever reaction after that injection. Authors thus concluded that it is the endothelial cell on the blood vessels of the brain’s surface (and not any other cell type located in liver or kidney or elsewhere in the body) that is necessary and sufficient to cause a fever reaction. 😊
DwN
Which brain cells are needed for fever
26 October 2022
Anders Törneholm
Researchers at Linköping University have identified in mice the cells in the blood vessels of the brain that are necessary for a fever reaction. The results have been published in PNAS, and answer a long-standing question as to which organs are involved in producing fever.
Man sitting by microscope.
“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 Anders Blomqvist.
“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.
Fever is the body’s response to infection or inflammation, and a defense mechanism against, for example, viruses and bacteria. When affected by infection or inflammation, the body releases molecules known as cytokines into the 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. But fever is just 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 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. A fever reaction has been initiated. It has, however, been unclear until now whether this is the only mechanism behind fever.
Filled a gap
It has previously been believed that prostaglandin must be produced also in certain cells of such organs as the liver and lungs in order to start a fever reaction. But the researchers at Linköping University (~200 km southwest of Stockholm) have now shown that this is 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 only ones required for a fever reaction to be produced.
“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 Anders Blomqvist.
The researchers have worked with gene-modified mice in which they have removed 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, producing in this way fever. The gene-modified mice did not show any fever reaction after the injection.
Stress raises temperature
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.
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, both the injections and the measurements can be made without causing stress for the animal, which means that the fever reaction can be observed more accurately.
“The general public has long believed that the body temperature of small animals is higher than that of humans and other large mammals, around 40 degrees F. But the measurements have been erroneous, because the animals became stressed during the process. The techniques we have used show that the mice have the same temperature as humans,” said Anders Blomqvist.
The article: Prostaglandin production selectively in brain endothelial cells is both necessary and sufficient for eliciting fever, Kiseko Shionoya, Anna Eskilsson, Anders Blomqvist, Proc Natl Acad Sci USA Vol. 119 No. 43, published online on 17 Oct 2022. DOI: 10.1073/pnas.2122562119