Rat area postrema microglial cells act as sensors for the toll-like receptor-4 agonist lipopolysaccharide

Wuchert, Florian; Ott, Daniela; Murgott, Jolanta; Rafalzik, Sandra; Hitzel, Norma; Roth, Joachim; Gerstberger, R.

doi:10.1016/j.jneuroim.2008.07.017

Cited by 50 publications

(48 citation statements)

References 61 publications

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“…The LPS-induced Ca 2ϩ signaling in cultured microglia was abolished by ruthenium red and preincubation with caffeine, thus suggesting the involvement of RyRs and caffeine-sensitive ER Ca 2ϩ store (29,1007). This response was not confirmed by others including our own observations.…”

Section: B Store-operated Ca 2؉ Entrycontrasting

confidence: 84%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,070

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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Section: B Store-operated Ca 2؉ Entrycontrasting

confidence: 84%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,070

2,981

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“…Although TNFα expression has been observed throughout the pituitary [71-73], the cellular phenotype of TNF-expressing cells has not been determined previously. The shape of TNFα staining resembled the one that had been shown earlier for microglia in other primary cell cultures in the so-called trans-golgi apparatus [39]. Moreover, the release of this particular cytokine was inhibited by the JAK-STAT inhibitor AG490, which was accompanied by reduced NF-IL6-IR.…”

Section: Discussionsupporting

confidence: 74%

“…Cells were stimulated with LPS (100 μg/mL) or PBS and incubated for 6 h. According to a preliminary time course experiment (data not shown) and results from other primary cell cultures, 6 h proved to be an ideal time point to detect TNFα immunreactivity and its release (16 independent experiments) into the supernatant [39]. In another set of experiments (3 independent experiments, 2 to 3 wells for each treatment), the JAK-STAT-inhibitor AG490 (N-Benzyl-3,4-dihydroxybenzylidenecyano-acetamide; 1,5 μg/μL, 5 mM; Enzo Life Sciences International Inc., PA, USA) or its diluent (25% Cremophor®EL, Polyoxyethylenglyceroltriricinoleat 35, DAC in PBS; into serum-free medium 1:50; Sigma-Aldrich, Munich, Germany) were used to preincubate cells 30 min before control or LPS stimulation.…”

Section: Methodsmentioning

confidence: 99%

“…In another set of experiments (3 independent experiments, 2 to 3 wells for each treatment), the JAK-STAT-inhibitor AG490 (N-Benzyl-3,4-dihydroxybenzylidenecyano-acetamide; 1,5 μg/μL, 5 mM; Enzo Life Sciences International Inc., PA, USA) or its diluent (25% Cremophor®EL, Polyoxyethylenglyceroltriricinoleat 35, DAC in PBS; into serum-free medium 1:50; Sigma-Aldrich, Munich, Germany) were used to preincubate cells 30 min before control or LPS stimulation. The cells of the anterior lobe of the pituitary were fixed with 4% freshly prepared paraformaldehyde (Merck) in PBS, pH 7.4, for 15 min at RT and immunocytochemistry was performed as previously reported [39] using the same antibodies and dilutions as indicated in Table 1. Supernatants were used for the determination of TNFα.…”

Section: Methodsmentioning

confidence: 99%

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Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain

Fuchs

Damm

Gerstberger

et al. 2013

J Neuroinflammation

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BackgroundThe transcription factor nuclear factor interleukin 6 (NF-IL6) is known to be activated by various inflammatory stimuli in the brain. Interestingly, we recently detected NF-IL6-activation within the hypothalamus-pituitary-adrenal (HPA)-axis of rats after systemic lipopolysaccharide (LPS)-injection. Thus, the aim of the present study was to investigate whether NF-IL6 is activated during either, inflammatory, or psychological stress in the rat brain.MethodsRats were challenged with either the inflammatory stimulus LPS (100 μg/kg, i.p.) or exposed to a novel environment. Core body temperature (Tb) and motor activity were monitored using telemetry, animals were killed at different time points, brains and blood removed, and primary cell cultures of the anterior pituitary lobe (AL) were investigated. Analyses were performed using immunohistochemistry, RT-PCR, and cytokine-specific bioassays.ResultsStress stimulation by a novel environment increased NF-IL6-immunoreactivity (IR) in the pituitary’s perivascular macrophages and hypothalamic paraventricular cells and a rise in Tb lasting approximately 2 h. LPS stimulation lead to NF-IL6-IR in several additional cell types including ACTH-IR-positive corticotrope cells in vivo and in vitro. Two other proinflammatory transcription factors, namely signal transducer and activator of transcription (STAT)3 and NFκB, were significantly activated and partially colocalized with NF-IL6-IR in cells of the AL only after LPS-stimulation, but not following psychological stress. In vitro NF-IL6-activation was associated with induction and secretion of TNFα in folliculostellate cells, which could be antagonized by the JAK-STAT-inhibitor AG490.ConclusionsWe revealed, for the first time, that NF-IL6 activation occurs not only during inflammatory LPS stimulation, but also during psychological stress, that is, a novel environment. Both stressors were associated with time-dependent activation of NF-IL6 in different cell types of the brain and the pituitary. Moreover, while NF-IL6-IR was partially linked to STAT3 and NFκB activation, TNFα production, and ACTH-IR after LPS stimulation; this was not the case after exposure to a novel environment, suggesting distinct underlying signaling pathways. Overall, NF-IL6 can be used as a broad activation marker in the brain and might be of interest for therapeutic approaches not only during inflammatory but also psychological stress.

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“…Combined with our findings that the SMF significantly reduced IL-6 expression in LPS-challenged BV-2 cells (Figure 6), it is possible that this reduction effect occurs via the IL-6-inhibited TNF-a expression in LPS-stimulated microglia (Figure 8). Wuchert et al (2008) found that the levels of IL-6 expressed by microglial cells were significantly attenuated by pre-incubating the cells with LPS before the start of the acute LPS stimulation. Although their report indicated that the central nervous system organs exhibited endotoxin tolerance, clinical application of endotoxin tolerance for controlling neuro-inflammation remains unavailable, because it is very difficult to control the location and concentration of low-level LPS injection accurately in the brain.…”

Section: Discussionmentioning

confidence: 96%

A static magnetic field attenuates lipopolysaccharide-induced neuro-inflammatory response via IL-6-mediated pathway

Shen

Huang²,

Yang³

et al. 2013

Electromagnetic Biology and Medicine

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An effective method for controlling brain damage and neurodegeneration caused by inflammation remains elusive. Down-expression of the lipopolysaccharide (LPS)-induced inflammatory cytokines resulting in endotoxin tolerance is reported as an alternative anti-infection treatment. Nonetheless, because the dosage and action site are hard to control, endotoxin tolerance caused by low-dose LPS injection in brain tissue may induce side effects. The aim of this study was to test the hypothesis that static magnetic fields (SMF) stimulate endotoxin tolerance in brain tissue. In this study, survival rate and pathological changes in brain tissues of LPS-challenged mice were examined with and without SMF treatment. In addition, the effects of SMF exposure on growth rate and cytokine expression of LPS-challenged BV-2 microglia cells were monitored. Our results showed that SMF pre-exposure had positive effects on the survival rate and histological outcomes of LPS-treated mice. Furthermore, SMF exposure significantly decreased IL-6 expression in BV-2 cells (p < 0.05) by a phenomenon similar to endotoxin tolerance. We suggest that SMF has potential as an alternative simulation source for controlling LPS-induced excess neuro-inflammatory response.

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Rat area postrema microglial cells act as sensors for the toll-like receptor-4 agonist lipopolysaccharide

Cited by 50 publications

References 61 publications

Physiology of Microglia

Physiology of Microglia

Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain

A static magnetic field attenuates lipopolysaccharide-induced neuro-inflammatory response via IL-6-mediated pathway

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