Slfn4 deficiency improves MAPK-mediated inflammation, oxidative stress, apoptosis and abates atherosclerosis progression in apolipoprotein E-deficient mice.

Abstract Background and aims Atherosclerosis, a progressive inflammatory disease characterized by elevated inflammation and lipid accumulation in the aortic endothelium, arises in part from the infiltration of inflammatory cells into the vascular wall. However, it is not fully defined how inflammatory cells, especially macrophages, affect the pathogenesis of atherosclerosis. Schlafen4 (Slfn4) mRNA is remarkably upregulated upon ox-LDL stimulation in macrophages. Nonetheless, the role of Slfn4 in foam cell formation remains unclear. Methods To determine whether and how Slfn4 regulates lesion macrophage function during atherosclerosis，we engineered ApoE–/–Slfn4–/– double-deficient mice on an ApoE–/– background and evaluated the deficiency of Slfn4 expression in atherosclerotic lesion formation in vivo. Results Our results demonstrate that total absence of SLFN4 and the bone marrow-restricted deletion of Slfn4 in ApoE–/– mice remarkably diminish inflammatory cell numbers within arterial plaques as well as limit development of atherosclerosis in moderate hypercholesterolemia condition. This is linked to a marked reduction in the expression of proinflammatory cytokines, the generation of the reactive oxygen species (ROS) and the apoptosis of cells. Furthermore, the activation of MAPKs and apoptosis signaling pathways is compromised in the absence of Slfn4. Conclusions These findings demonstrate a novel role of Slfn4 in modulating vascular inflammation and atherosclerosis, highlighting a new target for the related diseases.