Brain endothelial cells – prostaglandin E2 and fever
A study by Daniel Björk Wilhelms and colleagues from the Linköping University in Sweden, published in The Journal of Neuroscience, identifies the exact source and location where prostaglandins (the mediators that trigger fever) are produced in the brain during inflammation-induced fever.
The prostaglandin E2 (PgE2) was first proposed some 3-4 decades ago as the key factor for fever generation. In fact, the inhibition of prostaglandin synthesis represents the major mechanism of action for common antipyretic drugs, such as aspirin.
Eleven years ago he had his first breakthrough as a researcher when he uncovered the mechanism behind the formation of prostaglandin E2 during fever. These signaling molecules cannot pass the blood-brain barrier, the purpose of which is to protect the brain from hazardous substances. Engblom showed that instead, they could be synthesised from two enzymes in the blood vessels on the inside of the brain, before moving to the hypothalamus, where the body’s thermostat is located.
Previous research has mapped the anterior preoptic hypothalamus as the brain’s target region for fever-inducing PgE2. It is known that PgE2 in this area initiates a complex neuro-endocrine response during fever, and that the hypothalamus regulates body’s temperature through both heat production and heat loss’ control.
The precise source of PgE2 during fever induction, and, specifically, which cells are the critical interface in transmitting the pyrogenic signal from the periphery to the brain still remain subjects of debate.
Prostaglandins circulating in the blood are thought to be the major source, but it remains controversial whether PgE2 can actually pass from the blood into the brain. The other option is that PgE2 is produced from immune cells in the brain or it is generated by other cells inside rather than outside the blood-brain barrier (BBB).
The brain endothelium is a strong candidate for being the critical site of prostaglandin production, as immune challenge induces the production in these cells of both cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1) – the enzymes responsible for the generation of PgE2.
Of note, no cell-type-specific inhibition of brain endothelial prostaglandin synthesis has so far been performed, and it has not been known whether blockade of PGE2 synthesis in the brain endothelium would attenuate the febrile response.
Wilhelms et al., the authors of The Journal of Neuroscience study, tested this hypothesis by using transgenic mice with targeted, selective deletion of the genes encoding COX-2 and mPGES-1 in blood–brain barrier endothelial cells. These animals exhibited strongly attenuated febrile responses, indicating a pivotal role for brain endothelial cell PGE2 synthesis in the induction of inflammatory fever.
According to the researchers this indicates that prostaglandins are formed in the blood-brain barrier and demonstrates the crucial role of brain endothelial PgE2 production in the generation of fever.
Thus, this study shows the first example of a blunted systemic inflammatory symptom after a cell-type-specific intervention with prostaglandin synthesis. The Swedish team demonstrates that a full inflammation-induced fever requires COX-2 and mPGES-1 in brain endothelial cells and thus directly demonstrate an important role of brain endothelial PGE2 production in the generation of fever.
According to the authors this resolves, at least in part, a long-standing issue on which cells are the critical interface in transmitting the pyrogenic signal from the periphery to the brain.
A 2017 study by Anna Eskilsson et al. indicates that the febrile response is dependent on PGE2 synthesis by small- to medium-sized vessels in the hypothalamus but independent of global PGE2 synthesis in brain. Histological analysis showed that the deletion of cyclooxygenase-2 in brain endothelial cells occurred preferentially in small- and medium-sized vessels deep in the brain parenchyma, such as in the hypothalamus.
Of note, the magnitude of the febrile response was strongly correlated with the PGE2-synthesizing capacity in the hypothalamus, as reflected in the levels of Cox-2 mRNA, but was only weakly related to the PGE2 levels in the cerebrospinal fluid (CSF). Thus, the study demonstrates that local prostaglandin E2 (PGE2) production in deep brain areas, such as the hypothalamus, which is the site of thermoregulatory neurons, is critical for the febrile response to peripheral inflammation.