Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system

Godbout, Jonathan P.; Chen, J.; Abraham, Jayne; Richwine, Amy F.; Berg, Brian M.; Kelley, Keith W.; Johnson, Rodney W.

doi:10.1096/fj.05-3776fje

Cited by 740 publications

(776 citation statements)

References 59 publications

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“…28 The excessive production of reactive oxidative species (ROS) is associated with inflammation, 29 and aged rodents exhibited exaggerated neuroinflammation and memory deficits in response to OS. 30 We found a clear inflammatory landscape in hippocampus in old in comparison with young mice, which could be the…”

Section: Discussionmentioning

confidence: 68%

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

Palomera-Ávalos

Griñán-Ferré

Izquierdo

et al. 2017

Rejuvenation Research

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Inflammation and oxidative stress (OS) are key points in age progression. Both processes impact negatively in cognition and in brain functions. Resveratrol (RV) has been postulated as a potent antioxidant natural compound, with rejuvenating properties. Inducing a metabolic stress by high-fat (HF) diet in aged C56/BL6 (24 months) led to cognitive disturbances compared with control age mated and with young mice. These changes were prevented by RV. Molecular determinations demonstrated a significant increase in some inflammatory parameters (TNF-a, Cxcl10, IL-1, IL-6, and Ccl3) in old mice, but slight changes in OS machinery. RV mainly induced the recovery of the metabolically stressed animals. The study of key markers involved in senescence and rejuvenation (mitochondrial biogenesis and Sirt1-AMPK-PGC1-a) demonstrated that RV is also able to modulate the changes in these cellular metabolic pathways. Moreover, changes of epigenetic marks (methylation and acetylation) that are depending on OS were demonstrated. On the whole, results showed the importance of integrative role of different cellular mechanisms in the deleterious effects of age in cognition and the beneficial role of RV. The work presented in this study showed a wide range of processes modified in old age and by metabolic stress, weighting the importance of each one and the role of RV as a possible strategy for fighting against.

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Section: Discussionmentioning

confidence: 68%

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

Palomera-Ávalos

Griñán-Ferré

Izquierdo

et al. 2017

Rejuvenation Research

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“…In mice and other rodents, LMA can be used to evaluate sickness after immune activation [4][5] . Additionally, long-term LMA offers the ability to track movement over a 24 hr (or greater) period, allowing analysis of treatment-induced alterations in circadian behavior or disturbances in sleep/ wake patterns.…”

Section: Discussionmentioning

confidence: 99%

Mouse Short- and Long-term Locomotor Activity Analyzed by Video Tracking Software

York

Blevins

McNeil

et al. 2013

JoVE

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Locomotor activity (LMA) is a simple and easily performed measurement of behavior in mice and other rodents. Improvements in video tracking software (VTS) have allowed it to be coupled to LMA testing, dramatically improving specificity and sensitivity when compared to the line crossings method with manual scoring. In addition, VTS enables high-throughput experimentation. While similar to automated video tracking used for the open field test (OFT), LMA testing is unique in that it allows mice to remain in their home cage and does not utilize the anxiogenic stimulus of bright lighting during the active phase of the light-dark cycle. Traditionally, LMA has been used for short periods of time (mins), while longer movement studies (hrs-days) have often used implanted transmitters and biotelemetry. With the option of real-time tracking, long-, like short-term LMA testing, can now be conducted using videography. Long-term LMA testing requires a specialized, but easily constructed, cage so that food and water (which is usually positioned on the cage top) does not obstruct videography. Importantly, videography and VTS allows for the quantification of parameters, such as path of mouse movement, that are difficult or unfeasible to measure with line crossing and/or biotelemetry. In sum, LMA testing coupled to VTS affords a more complete description of mouse movement and the ability to examine locomotion over an extended period of time. Video LinkThe video component of this article can be found at http://www.jove.com/video/50252/ Protocol 1. Short-term LMA Set Up and Procedure 1. Short-term LMA cage set up 1. Test short-term LMA within the home cage of a single-housed mouse. To facilitate VTS-dependent image analysis, use bedding in high contrast with mouse color (i.e. dark colored bedding for white mice and light colored bedding for black mice). 2. During short-term LMA testing, cover cages with clear ¼ in Plexiglas with 11 x ¼ in diameter holes to support appropriate ventilation.2. Short-term LMA testing room 1. Test mice in a clean environment in which they have been acclimated to for at least 24 hr 8 . 2. To illuminate the testing environment, use brooder clamp lights with red bulbs (< 125 lumens). Prior to videography, adjust the angle and position of the lights to remove glare or reflections from the Plexiglas cage tops. 3. Remove or avoid room noise above 70 dB. Use a white noise generator if intermittent background noise is unavoidable during mouse testing. 4. Cover the testing surface upon which the cages are placed in the testing room with butcher or lab bench paper of similar color to the cage bedding, in case the cage floor is exposed during videography.3. Short-term LMA videography 1. Center and place a ceiling-mounted night vision-capable video camera with at least 120 GB of memory above the recording area in the testing room. Do not exceed the resolution capability of the VTS used by placing too many cages within the video camera view frame (e.g. Ethovision XT 7 by Noldus Information Technology (Leesbu...

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“…In some instances, however, peripheral infection results in an exaggerated brain cytokine response and behavioral pathology. For example, old mice that expressed high levels of inflammatory cytokines in the brain after peripheral injection of LPS remained anorectic longer (4), exhibited depression-like behavior longer (5), and experienced deficits in hippocampaldependent working memory not seen in young adult cohorts (6). Peripheral infection also exacerbated neurodegeneration in animal models of multiple sclerosis, Alzheimer's disease, and prion disease by inducing an exaggerated inflammatory cytokine response in the brain (7).…”

Section: Ipopolysaccharide (Lps) Is An Outer Membrane Componentmentioning

confidence: 99%

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

Jang¹,

Kelley

Johnson

2008

Proc. Natl. Acad. Sci. U.S.A.

321

192

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Luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce production of proinflammatory mediators in LPS-stimulated macrophages, fibroblasts, and intestinal epithelial cells. Because excessive production of proinflammatory cytokines by activated brain microglia can cause behavioral pathology and neurodegeneration, we sought to determine whether luteolin also regulates microglial cell production of a prototypic inflammatory cytokine, IL-6. Pretreatment of primary murine microlgia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. To determine how luteolin inhibited IL-6 production in microglia, EMSAs were performed to establish the effects of luteolin on LPS-induced binding of transcription factors to the NF-B and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-B DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of I B-␣ but inhibited JNK phosphorylation. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 h after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation.cytokines ͉ flavonoids ͉ MAPK ͉ brain ͉ neuroinflammation

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Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system

Cited by 740 publications

References 59 publications

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

Mouse Short- and Long-term Locomotor Activity Analyzed by Video Tracking Software

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

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