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Immune challenge by intraperitoneal administration of lipopolysaccharide directs gene expression in distinct blood-brain barrier cells toward enhanced prostaglandin E2 signaling
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Center for Hematology and Regenerative Medicine (HERM), Novum, Karolinska Institute, Huddinge, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
2015 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 48, 31-41 p.Article in journal (Refereed) Published
Abstract [en]

The cells constituting the blood-brain barrier are critical for the transduction of peripheral immune signals to the brain, but hitherto no comprehensive analysis of the signaling events that occur in these cells in response to a peripheral inflammatory stimulus has been performed. Here, we examined the inflammatory transcriptome in blood-brain barrier cells, including endothelial cells, pericytes, and perivascular macrophages, which were isolated by fluorescent-activated cell sorting, from non-immune-challenged mice and from mice stimulated by bacterial wall lipopolysaccharide. We show that endothelial cells and perivascular macrophages display distinct transcription profiles for inflammatory signaling and respond in distinct and often opposing ways to the immune stimulus. Thus, endothelial cells show induced PGE2 synthesis and transport with attenuation of PGE2 catabolism, increased expression of cytokine receptors and down-stream signaling molecules, and downregulation of adhesion molecules. In contrast, perivascular macrophages show downregulation of the synthesis of prostanoids other than PGE2 and of prostaglandin catabolism, but upregulation of interleukin-6 synthesis. Pericytes were largely unresponsive to the immune stimulation, with the exception of downregulation of proteins involved in pericyte-endothelial cell communication. While the endothelial cells account for most of the immune-induced gene expression changes in the blood-brain barrier, the response of the endothelial cells occurs in a concerted manner with that of the perivascular cells to elevate intracerebral levels of PGE2, hence emphasizing the critical role of PGE2 in immune-induced signal transduction across the blood-brain barrier.

Place, publisher, year, edition, pages
Academic Press, 2015. Vol. 48, 31-41 p.
National Category
Cell and Molecular Biology
URN: urn:nbn:se:liu:diva-114377DOI: 10.1016/j.bbi.2015.02.003ISI: 000358460700005PubMedID: 25678162OAI: diva2:789610

This work was supported by Grants from the Swedish Research Council (07879 to AB, and 22241 to HQ), the Swedish Cancer Foundation (13 0295 to AB), the Swedish Brain Foundation (to AB), the County Council of Ostergotland (to AMV), and Knut och Alice Wallenberg Foundation (WIRM to HQ).

Available from: 2015-02-19 Created: 2015-02-19 Last updated: 2016-08-19Bibliographically approved
In thesis
1. Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2
Open this publication in new window or tab >>Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and proinflammatory cytokines were among the first mediators to be identified to participate in the immuneto-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.

In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).

BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or non-hematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for pro-inflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.

Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcription-independent manner and that the profound gene expression changes that are seen in the CNS during inflammation are accordingly PGE2-independent.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 99 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1435
National Category
Cell and Molecular Biology Cell Biology
urn:nbn:se:liu:diva-114378 (URN)10.3384/diss.diva-114378 (DOI)978-91-7519-155-3 (print) (ISBN)
Public defence
2015-03-20, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
Available from: 2015-02-19 Created: 2015-02-19 Last updated: 2016-05-04Bibliographically approved

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Vasilache, Ana-MariaQian, HongBlomqvist, Anders
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Division of Cell BiologyFaculty of Health SciencesDepartment of Clinical Immunology and Transfusion MedicineDivision of Microbiology and Molecular Medicine
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