Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis

Eskilsson, Anna; Mirrasekhian, Elahe; Dufour, Sylvie; Schwaninger, Markus; Engblom, David; Blomqvist, Anders

doi:10.1523/jneurosci.3520-14.2014

Cited by 116 publications

(85 citation statements)

References 33 publications

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“…The present data confirm that prostaglandin production in brain endothelial cells is important for the febrile response (Engström et al, 2012;Wilhelms et al, 2014;Eskilsson et al, 2014a).…”

Section: Role Of Peripherally Produced Pge2 For the Febrile Responsesupporting

confidence: 87%

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E₂Synthesis in the Brain

et al. 2017

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Fever occurs upon binding of prostaglandin E2 (PGE2) to EP3 receptors in the median preoptic nucleus of the hypothalamus, but the origin of the pyrogenic PGE2 has not been clearly determined. Here, using mice of both sexes, we examined the role of local vs generalized PGE2 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, PGE2 levels in the cerebrospinal fluid were only weakly related to the magnitude of the febrile response, whereas the PGE2 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 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 PGE2 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 PGE2 onto its target neurons and not on the overall PGE2 production in the brain. Eskilsson et al., page #3 Significance statementBy using mice with selective deletion of prostaglandin synthesis in brain endothelial cells, we demonstrate 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. In contrast, PGE2 production in other brain areas and the overall PGE2 level in the brain do not influence the febrile response. Furthermore, 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 LPS. These data imply that the febrile response is dependent on the local release of PGE2 onto its target neurons, possibly by a paracrine mechanism.Eskilsson et al., page #4

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Section: Role Of Peripherally Produced Pge2 For the Febrile Responsesupporting

confidence: 87%

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E₂Synthesis in the Brain

et al. 2017

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“…IL--1β, TNF--α and IL--6 have been shown to be responsible cytokines in the induction of fever, and where IL--1β seems to be dependent on IL--6 to induce fever 81,109 . Blood borne cytokines may act directly at sites lacking the blood--brain barrier, they might induce secondary cytokine production in hypothalamus or might be actively transported in there 81 .…”

Section: Fevermentioning

confidence: 99%

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Hagbom¹

2015

Linköping University Medical Dissertations

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Rotavirus infections cause diarrhea and vomiting that can lead to severe dehydration. Despite extensive tissue damage and cell death, the inflammatory response is very limited. The focus of this thesis was to study pathophysiological mechanisms behind diarrhea and vomiting during rotavirus infection and also to investigate the mechanism behind the limited inflammatory response. An important discovery in this thesis was that rotavirus infection and the rotavirus toxin NSP4 stimulate release of the neurotransmitter serotonin from intestinal sensory enterochromaffin cells, in vitro and ex vivo. Interestingly, serotonin is known to be a mediator of both diarrhea and vomiting. Moreover, mice pups infected with rotavirus responded with central nervous system (CNS) activation in brain structures associated with vomiting, thus indicating a cross-talk between the gut and brain in rotavirus disease. Our finding that rotavirus infection activates the CNS led us to address the hypothesis that rotavirus infection not only activates the vagus nerve to stimulate vomiting, but also suppresses the inflammatory response via the cholinergic anti-inflammatory pathway, both of which are mediated by activated vagal afferent nerve signals into the brain stem. We found that mice lacking an intact vagus nerve, and mice lacking the α7 nicotine acetylcholine receptor (nAChR), being involved in cytokine suppression from macrophages, responded with a higher inflammatory response. Moreover, stimulated cytokine release from macrophages, by the rotavirus toxin NSP4, could be attenuated by nicotine, an agonist of the α7 nAChR. Thus, it seems most reasonable that the cholinergic anti-inflammatory pathway contributes to the limited inflammatory response during rotavirus infection. Moreover, rotavirus-infected mice displayed increased intestinal motility at the onset of diarrhea, which was not associated with increased intestinal permeability. The increased motility and diarrhea in infant mice could be attenuated by drugs acting on the enteric nervous system, indicating the importance and contribution of nerves in the rotavirus mediated disease. In conclusion, this thesis provides further insight into the pathophysiology of diarrhea and describe for the first time how rotavirus and host cross-talk to induce the vomiting reflex and limit inflammation. Results from these studies strongly support our hypothesis that serotonin and activation of the enteric nervous system and CNS contributes to diarrhea, vomiting and suppression of the inflammatory response in rotavirus disease

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“…The critical role of the endothelial cells is further supported by the finding that mice lacking the membrane-bound receptor for IL-6 on brain endothelial cells show attenuated fever after LPS administration as well as a strong reduction of COX-2 expression in the brain [79]. Recently it was also shown that deleting COX-2 or mPGES-1 specifically in brain endothelial cells strongly attenuates the fever response after LPS injection [80].…”

Section: The Blood Brain Barriermentioning

confidence: 93%

Mechanisms Behind Illness-Induced Anorexia

Nilsson¹

2016

Linköping University Medical Dissertations

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Loss of appetite is together with fever and malaise hallmarks of infection. Loosing appetite during an acute infection such as influenza does not result in any long-lasting effects, but loosing appetite during chronic diseases such as cancer or AIDS constitutes a risk factor for mortality. Food intake regulation during inflammation is orchestrated by the brain in response to peripheral inflammatory signals. It is known that expression of the prostaglandin synthesizing enzyme cyclooxygenase 2 (COX-2) is crucial for the mechanisms underlying inflammation-induced anorexia, and that prostaglandin E2 (PGE2) is involved in anorexia induced by interleukin-1 beta (IL-1β). In this thesis I examined the prostaglandin pathways proposed to be involved in anorexia. We show that acute anorexia is dependent on COX-2 expression, while cancer-induced anorexia is mediated by cyclooxygenase 1 (COX-1), at least in the initial stages, suggesting that the signaling pathways for chronic-and acute anorexia are distinct. We were able to demonstrate that the pathway underlying acute anorexia is distinct from that of fever, and that taste aversion is prostaglandin independent. We could also show that both acute and chronic anorexia-cachexia is dependent on expression of myeloid differentiation primary response gene (MyD88) in hematopoietic/myeloid cells. De generella slutsatser vi kan dra av studierna som ligger till grund för denna avhandling är att symptomen som vi upplever när vi blir sjuka, och som länge har ansetts ha samma bakomliggande signalvägar, till stor del signaleras till hjärnan på olika sätt. Aptitförlusten som uppkommer vid en infektion är inte alls lika beroende av ett specifikt prostaglandin, prostaglandin E2, som man tidigare trott, men en viktig faktor för att utveckla aptitförlust både vid akut-och kronisk sjukdom verkar vara MyD88-signallering i kroppens immunceller.Att kartlägga hur dessa signalvägar fungerar och vad som skiljer olika sjukdomssymptom åt är av stor vikt för utvecklingen av nya läkemedel. Dagens receptfria anti-inflammatoriska läkemedel är visserligen effektiva, men påverkar många av kroppens homeostatiska processer. Det är därför vanligt med allvarliga biverkningar såsom nedsatt hjärtfunktion och ökad risk för stroke och hjärtinfarkt, påverkan på njurfunktionen och magsår vid kronisk användning av dessa preparat. Önskvärt vore om det fanns läkemedel som endast påverkade de processer som missgynnar välmående.

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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

Cited by 116 publications

References 33 publications

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E₂Synthesis in the Brain

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E₂Synthesis in the Brain

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Mechanisms Behind Illness-Induced Anorexia

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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

Cited by 116 publications

References 33 publications

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E2Synthesis in the Brain

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E2Synthesis in the Brain

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Mechanisms Behind Illness-Induced Anorexia

Contact Info

Product

Resources

About

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E₂Synthesis in the Brain

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E₂Synthesis in the Brain