Interleukin-1 Mediates Neuroinflammatory Changes Associated With Diet-Induced Atherosclerosis

被引:45
作者
Denes, Adam [1 ]
Drake, Caroline [1 ]
Stordy, Jing [2 ]
Chamberlain, Janet [2 ]
McColl, Barry W. [3 ,4 ]
Gram, Hermann [6 ]
Crossman, David [2 ,5 ]
Francis, Sheila [2 ]
Allan, Stuart M. [1 ]
Rothwell, Nancy J. [1 ]
机构
[1] Univ Manchester, Fac Life Sci, Manchester, Lancs, England
[2] Univ Sheffield, Sch Med, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England
[3] Univ Edinburgh, Roslin Inst, Edinburgh EH8 9YL, Midlothian, Scotland
[4] Univ Edinburgh, RDSVS, Edinburgh EH8 9YL, Midlothian, Scotland
[5] Univ E Anglia, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England
[6] Novartis Inst BioMed Res, Basel, Switzerland
来源
JOURNAL OF THE AMERICAN HEART ASSOCIATION | 2012年 / 1卷 / 03期
基金
英国生物技术与生命科学研究理事会; 英国医学研究理事会;
关键词
interleukin-1; atherosclerosis; cerebrovascular inflammation; leukocyte; microglia; BRAIN INFLAMMATION; DISEASE; MICE; CHOLESTEROL; DEPRESSION; OBESITY; CELLS;
D O I
10.1161/JAHA.112.002006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Systemic inflammation contributes to brain pathology in cerebrovascular disease through mechanisms that are poorly understood. Methods and Results-Here we show that atherosclerosis, a major systemic inflammatory disease, is associated with severe cerebrovascular inflammation in mice and that this effect is mediated by the proinflammatory cytokine interleukin-1 (IL-1). Apolipoprotein E-deficient mice fed Paigen or Western diets develop vascular inflammation, microglial activation, and leukocyte recruitment in the brain, which are absent in apolipoprotein E-deficient mice crossed with IL-1 type 1 receptor-deficient mice. Systemic neutralization of IL-1 beta with an anti-IL-1 beta antibody reversed aortic plaque formation (by 34% after a Paigen and 45% after a Western diet) and reduced inflammatory cytokine expression in peripheral organs. Central, lipid accumulation-associated leukocyte infiltration into the choroid plexus was reversed by IL-1 beta antibody administration. Animals fed a Western diet showed 57% lower vascular inflammation in the brain than that of mice fed a Paigen diet, and this was reduced further by 24% after IL-1 beta antibody administration. Conclusions-These results indicate that IL-1 is a key driver of systemically mediated cerebrovascular inflammation and that interventions against IL-1 beta could be therapeutically useful in atherosclerosis, dementia, or stroke.
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页数:11
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