IRF2BP2, a Novel Transcriptional Regulator of Innate Immunity, Cholesterol Metabolism and Atherosclerosis

Abstract

Introduction: Increased activation of inflammatory pathways is associated with elevated metabolic stress, which leads to a constellation of metabolic pathologies like fatty liver, insulin resistance and atherosclerosis. Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a novel transcription co-factor that binds to and inhibits two main pro-inflammatory transcription factors, IRF2 and NFAT1. IRF2BP2 genetic variants are also linked to increased human serum cholesterol level in GWAS studies. Therefore, we hypothesized that IRF2BP2 may inhibit macrophage polarization to pro-inflammatory phenotype and considering the remarkable overlap between inflammatory and metabolic sensors, alter their metabolic function. We sought to determine if specific ablation IRF2BP2 in the mouse myeloid lineage (IRF2BP2MKO) leads to development of metabolic symptoms and alters the risk of atherosclerosis. Results: Our results indicate that IRF2BP2 ablation impairs macrophage polarization to the anti-inflammatory phenotype. IRF2BP2MKO bone marrow derived macrophages (BMDM) show increased oxidized LDL-cholesterol uptake and decreased cholesterol efflux. Also, mice with specific ablation of IRF2BP2 in macrophages are more susceptible to obesity, insulin resistance and hepatic steatosis compared to control mice, when fed high fat diet (HFD). However, LDLR-/- mice transplanted with IRF2BP2MKO bone marrow demonstrate similar extent of atherosclerotic lesions compared to LDLR-/- mice transplanted with control bone marrow, reflecting increased IRF2BP2MKO macrophage apoptosis. Conclusion: In conclusion, this is the first study to identify the metabolic and inflammatory functions of IRF2BP2 protein in macrophages, with important implications in metabolic syndrome and atherosclerosis.