IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis
Rationale: Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans.
Objective: To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans.
Methods and Results: We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated LDL-receptor null recipient mice and in ApoE null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux due to their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor KLF2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of KLF2. Importantly, restoring KLF2 in IRF2BP2-deficient macrophages attenuated M1-inflammatory and rescued M2-anti-inflammatory gene activation, and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1,066 angiographic cases and 1,011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3' UTR of human IRF2BP2 mRNA had a higher risk of coronary artery disease (CAD) (recessive model, odds ratio (95%CI) = 1.560 (1.179-2.065), p=1.73E-03) and had lower IRF2BP2 (and KLF2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies.
Conclusions: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice and a deletion variant that lowers IRF2BP2 expression predisposes to CAD in humans.
- Received December 3, 2014.
- Revision received July 13, 2015.
- Accepted July 17, 2015.