Interleukin-1 mediates neuroinflammatory changes associated with diet-induced atherosclerosis.

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.