TAK1 in brain endothelial cells mediates fever and lethargy

Ridder, Dirk A.; Lang, Ming-Fei; Salinin, Sergei; Röderer, Jan-Peter; Struss, Marcel; Maser-Gluth, Christiane; Schwaninger, Markus

doi:10.1084/jem.20110398

Cited by 109 publications

(157 citation statements)

References 30 publications

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“…Blood-borne IL-1β signaling to CNS is completely dependent on endothelial IL-1R1 (Ching et al, 2007), which at BBB was also shown to be highly expressed on endothelial cells and not on perivascular cells (Konsman et al, 2004). A later study in which the brain endothelial IL-1β signaling was specifically targeted by TAK1 deletion in brain endothelial cells resulted in blunted fever response and decreased locomotion (lethargy) (Ridder et al, 2011). However, intraperitoneally injected IL-1β may signal to CNS through other pathways, probably by activating peripheral macrophages (Ching et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…These studies include work on TLR4 chimeric mice (Chakravarty and Herkenham, 2005;Steiner et al, 2006b), endothelial specific IL-1R1 KO mice (Ching et al, 2007), brain endothelial TAK1 KO mice, i.e. specific brain endothelial IL-1 signaling blockage (Ridder et al, 2011), and MyD88 chimeric mice (Gosselin and Rivest, 2008) (Figure 9). …”

Section: Discussionmentioning

confidence: 99%

“…NF-kB activation induces the expression of well over 150 genes, for example inflammation-related genes like IL-1, IL-6, TNF-alpha, cell adhesion molecules (E-selectin, ICAM-1, VCAM-1, fibronectin), and prostaglandin synthases (phospholipase A2, cyclooxygenase-2) (comprehensive list in Table 1 of Kumar et al, 2004). Interestingly, recent reports have found a TAK1 independent NF-kB activation diverging at TRAF6 (Yamazaki et al, 2009) as well as a predominant NF-kB independent TAK1-dependent COX-2 upregulation, through p38 MAPK and c-Jun activation, in brain endothelial cells (Ridder et al, 2011). These later findings raise questions about the complexity and degree of specialization of the brain endothelial cells.…”

Section: General Remarks On the Main Transcription Factors Of Inflammmentioning

confidence: 99%

“…Two main opposing views emerged, one supporting the endothelial cells (Cao et al, 1995;Ek et al, 2001;Matsumura et al, 1998;Yamagata et al, 2001) and the other favoring the perivascular macrophages (Breder and Saper, 1996;Elmquist et al, 1997a;Schiltz and Sawchenko, 2002). To address this question, we (paper I) Hamzic et al, 2013b;Matsuwaki et al, 2014;Wilhelms et al, 2014) and other groups (Chakravarty and Herkenham, 2005;Ching et al, 2007;Gosselin and Rivest, 2008;Ridder et al, 2011) have developed complex transgenic mice models that allowed in vivo analysis of one gene in a BBB cell population at a time (reviewed with paper I).…”

Section: The Bbb As An Interface For Immune Signal-transductionmentioning

confidence: 99%

“…In this thesis only global transgenic mice were used (Table 1); however several important studies in immune-to-brain signaling have used conditional transgenic mice Ridder et al, 2011;Wilhelms et al, 2014). Chimeric mice were generated to differentiate between hematopoietic and non-hematopoietic production of PGE2.…”

Section: Mice Strainsmentioning

confidence: 99%

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Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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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 pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-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 nonhematopoietic 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 proinflammatory 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 transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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