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Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-2245-3396
Institute Curie, France.
Medical University of Lubeck, Germany.
Show others and affiliations
2014 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 48, p. 15957-15961Article in journal (Refereed) Published
Abstract [en]

The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Herewegenerated mice with deletion of themembranebound IL-6 receptor alpha (IL-6R alpha) onneural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6R alpha on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6R alpha in the brain endothelium plays an important role. Hence deletion of IL-6R alpha on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R alpha on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines.

Place, publisher, year, edition, pages
Society for Neuroscience , 2014. Vol. 34, no 48, p. 15957-15961
Keywords [en]
blood-brain barrier; cell-specific gene deletions; fever; interleukin-6; prostaglandins; STAT3
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-113199DOI: 10.1523/JNEUROSCI.3520-14.2014ISI: 000345923600013PubMedID: 25429137OAI: oai:DiVA.org:liu-113199DiVA, id: diva2:779792
Note

Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County CouncilO Ostergotland

Available from: 2015-01-13 Created: 2015-01-12 Last updated: 2020-01-08
In thesis
1. Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever
Open this publication in new window or tab >>Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fever is a cardinal sign of inflammation and is evolutionary conserved. Fever is known to be beneficial during acute inflammation, but over time and if very high it can be detrimental. The signaling pathways by which fever is initiated by the brain and the peripheral mechanisms through which the temperature increase is generated were studied from several point of views. Fever is known to be dependent on prostaglandin E2 (PGE2) binding to its receptors in the median preoptic nucleus of the hypothalamus, which signals to the brainstem and through sympathetic nerves to heat conserving and heat producing effector organs. This thesis focuses on identifying the cells that produce the PGE2 critical for the fever response; showing where in the brain the critical PGE2 production takes place; demonstrating how peripheral inflammation activates these cells to produce PGE2; and finally, identifying the effector mechanisms behind the temperature elevation in fever. By using a newly developed specific antibody we showed that the enzyme responsible for the terminal step in the production of PGE2, microsomal prostaglandin E-synthase 1 (mPGES-1), is expressed in endothelial cells of brain blood vessels in mice where it is co-expressed with the enzyme cyclooxygenase-2 (Cox-2), which is known to be induced in these cells and to be rate limiting for the PGE2 production. The mPGES-1 enzyme was also expressed in several other cell types and structures which however did not express Cox-2, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. The role of the mPGES-1 in these other cells/structures remains unknown. Next, by using mice with selective deletion of Cox-2 in brain endothelial cells, we showed that local PGE2 production in deep brain areas, such as the hypothalamus, is critical for the febrile response to peripheral inflammation. In contrast, PGE2 production in other brain areas and the overall PGE2 level in the brain were not critical for the febrile response. Partly restoring the PGE2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to an intraperitoneal injection of bacterial wall lipopolysaccharide (LPS). The data show that the febrile response is dependent on the local release of PGE2 onto its target neurons, possibly by a paracrine mechanism. Deletion of the receptor for the pyrogenic cytokine IL-6 on brain endothelial cells, but not on neurons or peripheral nerves, strongly attenuated the febrile response to LPS and reduced the induction of the Cox-2 expression in the hypothalamus. Furthermore, mice deficient of the IL- 6Rα gene in the brain endothelial cells showed a reduced SOCS3 mRNA induction, whereas IκB mRNA-levels were unaffected, suggesting that the IL-6 signaling occurs via STAT3 activation and not signaling through the transcription factor NF-κB. This idea was confirmed by the observation of attenuated fever in mice deficient of STAT3 in brain endothelial cells. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R on brain endothelial cells to induce prostaglandin synthesis in these cells. Finally, we demonstrate that mice with genetic deletion of uncoupling protein-1 (UCP-1), hence lacking functional brown adipose tissue, had a normal fever response to LPS, and that LPS caused no activation of brown adipose tissue in wild type mice. However, blocking peripheral cutaneous vasoconstriction resulted in a blunted fever response to LPS, suggesting that heat conservation, possibly together with shivering or non-shivering thermogenesis in the musculature, is responsible for the generation of immune-induced fever, whereas brown adipose tissue thermogenesis is not involved.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. p. 44
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1724
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-163003 (URN)10.3384/diss.diva-163003 (DOI)9789179299361 (ISBN)
Public defence
2020-02-14, Hasselqvistsalen, Building 511 Campus US, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-24Bibliographically approved

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