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- Eskilsson, Anna, 1986-
(författare)
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Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Mirrasekhian, Elahe, 1978-
(författare)
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Immune-to-Brain Signaling in Fever : The Brain Endothelium as Interface
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fever is a brain-regulated elevation of body temperature that occurs in response to infectious and non-infectious stimuli. During inflammatory episodes, circulating cytokines that are released by activated immune cells, trigger the induction of cyclooxygenase (COX)-2 in the ventromedial preoptic area of the hypothalamus (the thermoregulation center). COX-2-dependent-prostaglandin (PG)E2 synthesis is essential for the generation of fever and upon an immune challenge, it is induced in several cells within the brain including the brain endothelial cells and perivascular macrophages. However, due to lack of experimental models with cell type-specific modulation of PGE2 synthesizing enzymes, the cellular source of pyrogenic PGE2 and its induction mechanism(s) remained obscure. Using such technology, we showed that the brain endothelium is the cellular source of pyrogenic PGE2 and that activation of brain endothelial IL-6 receptors by circulating IL-6 is critical for the PGE2 induction.Inhibition of PGE2 synthesis is assumed to be the mode of action of many antipyretic drugs, possibly including paracetamol. Given that paracetamol at a high dose has been shown to induce hypothermia by activation of the transient receptor potential ankyrin 1 (TRPA1) ion channel, we examined whether the antipyretic effect of paracetamol is also TRPA1 dependent. Our findings revealed that the antipyretic effect of paracetamol is independent of TRPA1 and associated with inhibition of the PGE2 synthesis in the brain.This thesis provides new insight into the molecular mechanism behind the febrile response in which the peripheral circulating IL-6 communicates with the brain by induction of pyrogenic PGE2 in the brain endothelium. It also demonstrates that the antipyretic effect of paracetamol is exerted by inhibition of the PGE2 synthesis in the brain.
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