Stage-dependent differential effects of interleukin-1 isoforms on experimental atherosclerosis

Aims Targeting interleukin-1 (IL-1) represents a novel therapeutic approach to atherosclerosis. CANTOS demonstrated the benefits of IL-1 beta neutralization in patients post-myocardial infarction with residual inflammatory risk. Yet, some mouse data have shown a prominent role of IL-1 alpha rather than IL-1 beta in atherosclerosis, or even a deleterious effect of IL-1 on outward arterial remodelling in atherosclerosis-susceptible mice. To shed light on these disparate results, this study investigated the effect of neutralizing IL-1 alpha or/and IL-1 beta isoforms starting either early in atherogenesis or later in ApoE(-/-) mice with established atheroma. Methods and results The neutralization of IL-1 alpha or of both IL-1 isoforms impaired outward remodelling during early atherogenesis as assessed by micro-computed tomographic and histologic assessment. In contrast, the neutralization of IL-1 beta did not impair outward remodelling either during early atherogenesis or in mice with established lesions. Interleukin-1 beta inhibition promoted a slant of blood monocytes towards a less inflammatory state during atherogenesis, reduced the size of established atheromata, and increased plasma levels of IL-10 without limiting outward remodelling of brachiocephalic arteries. Conclusion This study established a pivotal role for IL-1 alpha in the remodelling of arteries during early experimental atherogenesis, whereas IL-1 beta drives inflammation during atherogenesis and the evolution of advanced atheroma in mice.