Oxidized Low‐Density Lipoprotein (OxLDL)–Treated Dendritic Cells Promote Activation of T Cells in Human Atherosclerotic Plaque and Blood, Which Is Repressed by Statins: microRNA let‐7c Is Integral to the Effect

Abstract

Background Activated T cells and dendritic cells ( DC s) are colocalized in atherosclerotic plaques in association with plaque rupture. Oxidized low‐density lipoprotein (ox LDL ) promotes immune activation and inflammation. We studied the effects of statins (atorvastatin and simvastatin) on human DC maturation and T‐cell activation. Methods and Results Human peripheral blood monocytes were differentiated to DC s and stimulated with ox LDL . T cells were isolated from carotid endarterectomy specimens from patients undergoing carotid endarterectomy or from healthy individuals. Naïve T cells were cocultured with pretreated DC s. The effects of statin were studied. Ox LDL induced DC maturation and T‐cell activation. Ox LDL induced atherogenic heat shock proteins ( HSP ) 60 and 90 and decreased potentially atheroprotective heat shock protein 27, effects restored by atorvastatin. T cells exposed to ox LDL ‐treated DC s produced interferon‐γ and interleukin ( IL )‐17. Atorvastatin and simvastatin suppressed the DC maturation showing lower expression of CD 80, CD 83, and CD 86, and limited their production of tumor necrosis factor‐α, IL ‐1β and IL ‐6, and increased transforming growth factor‐β and IL ‐10 secretion. Statin‐treated DC s inhibited Th1 and/or Th17 polarization by downregulation of transcriptional factors T‐bet and ROR γt expression, and induced T regulatory cells with IL ‐10 production. Ox LDL ‐induced mi RNA let7c and phosphorylation of Akt and ERK were repressed by statins. Let‐7c had a pivotal role in mediating effect of ox LDL . Experiments on T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar results. Conclusions Statins repress human DC maturation induced by ox LDL , limit T‐cell activation, and repress an atherogenic heat shock protein profile and promote induction of T regulatory cells. Micro RNA let‐7c is integral to the effects.