Myeloid-specific IκB kinase ß deficiency decreases atherosclerosis in low-density lipoprotein receptor-deficient mice.

OBJECTIVE: Inflammatory responses are the driving force of atherosclerosis development. IκB kinase ß (IKKß), a central coordinator in inflammation through regulation of nuclear factor-κB, has been implicated in the pathogenesis of atherosclerosis. Macrophages play an essential role in the initiation and progression of atherosclerosis, yet the role of macrophage IKKß in atherosclerosis remains elusive and controversial. This study aims to investigate the impact of IKKß expression on macrophage functions and to assess the effect of myeloid-specific IKKß deletion on atherosclerosis development. METHODS AND RESULTS: To explore the issue of macrophage IKKß involvement of atherogenesis, we generated myeloid-specific IKKß-deficient low-density lipoprotein receptor-deficient mice (IKKß(ΔMye)LDLR(-/-)). Deficiency of IKKß in myeloid cells did not affect plasma lipid levels but significantly decreased diet-induced atherosclerotic lesion areas in the aortic root, brachiocephalic artery, and aortic arch of low-density lipoprotein receptor-deficient mice. Ablation of myeloid IKKß attenuated macrophage inflammatory responses and decreased atherosclerotic lesional inflammation. Furthermore, deficiency of IKKß decreased adhesion, migration, and lipid uptake in macrophages. CONCLUSIONS: The present study demonstrates a pivotal role for myeloid IKKß expression in atherosclerosis by modulating macrophage functions involved in atherogenesis. These results suggest that inhibiting nuclear factor-κB activation in macrophages may represent a feasible approach to combat atherosclerosis.