ORIGINAL RESEARCH 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 cere-brovascular inflammation inmice and that this effect ismediated 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-1β with an anti–IL-1β antibody reversed aortic plaque formation (by 34 % after a Paigen and 45 % after a Western diet) and re-duced inflammatory cytokine expression in peripheral organs. Central, lipid accumulation–associated leukocyte infiltration into the choroid plexus was reversed by IL-1β 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-1β antibody administration. Conclusions—-These results indicate that IL-1 is a key driver of systemically mediated cerebrovascular inflammation and that inter-ventions against IL-1β could be therapeutically useful in atherosclerosis, dementia, or stroke. ( J AmHeart Assoc. 2012;1:e002006 doi: 10.1161/JAHA.112.002006.) Key Words: interleukin-1 atherosclerosis cerebrovascular inflammation leukocyte microglia I nflammation is a key driver of cardiovascular and cere-brovascular disease, including atherosclerosis, and con