Caspase 1 deficiency reduces inflammation-induced brain transcription

Mastronardi, Claudio A.; Whelan, Fiona; Yıldız, Özlem; Hannestad, Jonas; Elashoff, David; McCann, Samuel M.; Licinio, Júlio; Wong, Ma-Li

doi:10.1073/pnas.0701366104

Cited by 41 publications

(48 citation statements)

References 57 publications

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“…In response to emotional stress and in the absence of iPGE2 (Figure 2 in paper IV), both WT and KO mice displayed increased core body temperature and an up-regulation of HSPs. In conclusion, HSPs were independent of iPGE2, but dependent on the increased body temperature, which implied that inflammation-induced PGE2 regulates few, if any, of the gene expression changes that are seen in the CNS during systemic inflammation (Hamzic et al, 2013a;Mastronardi et al, 2007;Reyes et al, 2003).…”

Section: Minor Changes In Gene Expression In the Mouse Preoptic Hypotmentioning

confidence: 89%

“…The critical difference is that KO mice lack iPGE2 and thus display no fever (Engblom et al, 2003) and they also show attenuated HPA activation (Elander et al, 2009), and abolished conditioned place aversion (Fritz, 2012). The very low fold changes that was seen in induced gene expression between the two genotypes differ from the strong LPS effect seen in the mouse brain (Hamzic et al, 2013a;Mastronardi et al, 2007;Reyes et al, 2003). To control that the small differences seen in induced gene expression between genotypes were not due to a general lack of responsiveness to the LPS treatment, we also examined the LPS-induced induction by comparing gene expression in LPS-treated WT mice with that in saline injected WT mice.…”

Section: Discussionmentioning

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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Section: Minor Changes In Gene Expression In the Mouse Preoptic Hypotmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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

Vasilache¹

2015

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“…Among them, IL-1β and TNF-α play important roles in the pathology of depression [34,39] . For example, infusions of IL-1β or TNF-α into wild-type mice evokes depressive behavior [79] , whereas mice lacking caspase-1 (an enzyme essential for IL-1 synthesis) display reduced "sickness behavior" [80] . Further-…”

Section: Brain Cytokines Act As Executors In the Association Between mentioning

confidence: 99%

Using optogenetics to translate the “inflammatory dialogue” between heart and brain in the context of stress

Cheng¹,

Zhang

et al. 2012

Neurosci. Bull.

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Abstract:Inflammatory processes are an integral part of the stress response and are likely to result from a programmed adaptation that is vital to the organism's survival and well-being. The whole inflammatory response is mediated by largely overlapping circuits in the limbic forebrain, hypothalamus and brainstem, but is also under the control of the neuroendocrine and autonomic nervous systems. Genetically predisposed individuals who fail to tune the respective contributions of the two systems in accordance with stressor modality and intensity after adverse experiences can be at risk for stress-related psychiatric disorders and cardiovascular diseases. Altered glucocorticoid (GC) homeostasis due to GC resistance leads to the failure of neural and negative feedback regulation of the hypothalamic-pituitary-adrenal axis during chronic inflammation, and this might be the mechanism underlying the ensuing brain and heart diseases and the high prevalence of co-morbidity between the two systems. By the combined use of light and genetically-encoded lightsensitive proteins, optogenetics allows cell-type-specific, fast (millisecond-scale) control of precisely defined events in biological systems. This method is an important breakthrough to explore the causality between neural activity patterns and behavioral profiles relevant to anxiety, depression, autism and schizophrenia. Optogenetics also helps to understand the "inflammatory dialogue", the inflammatory processes in psychiatric disorders and cardiovascular diseases, shared by heart and brain in the context of stress.

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“…Furthermore, supporting data on the therapeutic effects of antiinflammatory drugs, particularly those that penetrate the blood-brain barrier (BBB), in mental disease are lacking; therefore, studies on the inflammatory mediators in the brain, and their effect on sustained production of secondary inflammatory mediators and on the integrity of the BBB, become very important. In a recent issue of PNAS, Mastronardi et al (1) provide evidence not only for a single inflammatory mediator being elevated in the brain, but also for up-regulation of an entire inflammatory cascade. They also describe a mechanism by which peripheral immune-competent cells are attracted to the brain, which may explain how the BBB could become compromised.…”

mentioning

confidence: 99%