In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 37, No. 19 ( 2017-05-10), p. 5035-5044
Abstract:
Fever occurs upon binding of prostaglandin E 2 (PGE 2 ) to EP 3 receptors in the median preoptic nucleus of the hypothalamus, but the origin of the pyrogenic PGE 2 has not been clearly determined. Here, using mice of both sexes, we examined the role of local versus generalized PGE 2 production in the brain for the febrile response. In wild-type mice and in mice with genetic deletion of the prostaglandin synthesizing enzyme cyclooxygenase-2 in the brain endothelium, generated with an inducible CreER T2 under the Slco1c1 promoter, PGE 2 levels in the CSF were only weakly related to the magnitude of the febrile response, whereas the PGE 2 synthesizing capacity in the hypothalamus, as reflected in the levels of cyclooxygenase-2 mRNA, showed strong correlation with the immune-induced fever. 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, whereas larger vessels, and particularly those close to the neocortical surface and in the meninges, were left unaffected, hence leaving PGE 2 synthesis largely intact in major parts of the brain while significantly reducing it in the region critical for the febrile response. Furthermore, injection of a virus vector expressing microsomal prostaglandin E synthase-1 (mPGES-1) into the median preoptic nucleus of fever-refractive mPGES-1 knock-out mice, resulted in a temperature elevation in response to LPS. We conclude that the febrile response is dependent on local release of PGE 2 onto its target neurons and not on the overall PGE 2 production in the brain. SIGNIFICANCE STATEMENT By using mice with selective deletion of prostaglandin synthesis in brain endothelial cells, we demonstrate that local prostaglandin E 2 (PGE 2 ) 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. In contrast, PGE 2 production in other brain areas and the overall PGE 2 level in the brain do not influence the febrile response. Furthermore, partly restoring the PGE 2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to LPS. These data imply that the febrile response is dependent on the local release of PGE 2 onto its target neurons, possibly by a paracrine mechanism.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.3846-16.2017
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2017
detail.hit.zdb_id:
1475274-8
SSG:
12
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