IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis

Abstract

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. Objectives: 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 low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 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 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3′ untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179–2.065], P =1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies. Conclusion: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.

Loss of IRF2BP2 in Microglia Increases Inflammation and Functional Deficits after Focal Ischemic Brain Injury

“…IRF2BP2-deficient macrophages have a heightened inflammatory response when challenged with lipopolysaccharides (LPS), whereas their response to interleukin-4 (IL4)-induced activation of anti-inflammatory M2 genes is impaired. Our studies further demonstrated that ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans (Chen et al, 2015). Given known differences in basal gene expression between macrophages and microglia (Hickman et al, 2013), it was important to determine whether IRF2BP2 controls microglia polarization in a similar fashion as in macrophages.…”

“…We recently identified a novel function of IRF2BP2 as a key regulator of macrophage polarization: it promotes activation of anti-inflammatory (M2) marker genes and inhibits pro-inflammatory (M1) markers (Chen et al, 2015). Bone Marrow-derived Macrophages (BMDMs) isolated from LysMCre/IRF2BP2flox mice do not express IRF2BP2 and have impaired cholesterol handling due to their inflammatory phenotype.…”

Monocyte-Macrophages and T Cells in Atherosclerosis

“…Macrophage functions can vary widely depending on a number of interacting variables and factors, including local environment (“tissue niche”) (Gosselin et al, 2014; Lavin et al, 2014); intracellular energy metabolism (Van den Bossche et al, 2017); gut microbiota metabolites (Wang et al, 2011); and genetic and epigenetic factors, including non-coding RNAs (Erbilgin et al, 2013; Chen et al, 2015; Wu et al, 2016; Amit et al, 2016; Phan et al, 2017; Aryal et al, 2014). These factors program macrophages for functions on a spectrum from inflammatory and host defense to resolution and repair.…”

IRF2BP2 transcriptional repressor restrains naive CD4 T cell activation and clonal expansion induced by TCR triggering

“…Although the majority of works available in the literature proposes a role for IRF2BP2 as a repressor in the regulation of diverse genes [4][5][6][7][8][9], there is some evidence that IRF2BP2 may also act as a positive regulator of gene expression [10,11]. The mechanisms by which IRF2BP2 mediates its repression or induction in the course of gene-expression regulation have not been established and may involve interaction with the DNA and/or with different proteins that vary according to the context.…”

“…Indeed, this protein has been described as a participant in at least 2 distinct transcriptional repressor complexes, in which it is dependent on either its zinc finger or RING domains [8,9]. As IRF2BP2 is ubiquitously expressed and has diverse roles described in several biologic contexts [4][5][6][7][8][9][10][11], more studies are necessary to investigate its possible roles in different cell types.…”