Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α

ObjectiveInterleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1’s. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE−/− mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production.MethodsWe generated strains of double knock-out (KO) mice (apoE−/−/IL-1α−/− and apoE−/−/IL-1β−/−) and created chimeras consisting of apoE−/− mice reconstituted with bone marrow-derived cells from apoE−/−/IL-1+/+, apoE−/−/IL-1α−/− and apoE−/−/IL-1β−/−.ResultsThe areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE−/− mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE−/− mice transplanted with IL-1β−/− or IL-1α−/− cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α−/− macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (−50%) and 2–3-fold higher levels of the anti-inflammatory cytokine IL-10.ConclusionWe show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.

Research highlights
► IL-1α or IL-1β deficiency inhibited atherogenesis in apoE-deficient mice.
► IL-1α or IL-1β deficiency in bone marrow-derived cells was sufficient to inhibit atherogenesis.
► IL-1α deficiency in macrophages did not affect LDL degradation.
► IL-1α deficient macrophages secreted less IL-1β and more IL-10.