The pleiotropic benefits of statins include the ability to reduce CD47 and amplify the effect of pro-efferocytic therapies in atherosclerosis

The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. In the present study, RNA-sequencing designed to investigate gene expression patterns after CD47–SIRPα inhibition identifies a link of statins, efferocytosis and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NF-κB1 p50 and suppressing the expression of the critical ‘don’t-eat-me’ molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47–SIRPα blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of prophagocytic therapies independently of any lipid-lowering effect. Jarr and colleagues show that statins augment efferocytosis by inhibiting the nuclear translocation of NF-κB1 p50 and suppressing the expression of the key ‘don’t-eat-me’ molecule CD47, which in part explains the pleiotropic effects of statins and provides a basis for future translational efforts.