Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1β and IL-6

Journal of Neuroinflammation

Colm Cunningham¹  Donal T Skelly¹  Carol L Murray¹ 

[1] School of Biochemistry and Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Rep. of Ireland

关键词: IL-1β;    Alzheimer's disease;    inflammation;    systemic;    neurodegeneration;    chronic;    dexamethasone;    priming;    microglia;   

Others  :  1213346
DOI  :  10.1186/1742-2094-8-50

 received in 2011-03-24, accepted in 2011-05-17,  发布年份 2011

【 摘 要 】

Background

Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses.

Methods

ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined.

Results

LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1β and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1β protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 μg/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response.

Conclusions

These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to transduce systemic inflammatory signals into the brain or to exacerbate existing pathology.

【 授权许可】

   
2011 Murray et al; licensee BioMed Central Ltd.

【 图 表 】

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