Role of allograft inflammatory factor-1 (Aif-1) in macrophage activity, atherosclerosis, and obesity

Abstract

Cardiovascular disease (CVD) is the leading cause of death in developed societies. The main contributor to CVD is atherosclerosis, a complex disease in which accumulation of lipoprotein deposits in arterial walls results in a chronic inflammatory response that leads to plaque formation. The macrophage, in particular, has been shown to play a fundamental role in the inflammatory response that promotes atherosclerosis. The Allograft Inflammatory Factor (Aif-1), also known as Ionized Binding Adapter-1 (Iba-1), is a 17 kDa cytoplasmic EF-hand protein expressed in vascular lesions with atherogenic characteristics. Although substantial evidence links Aif-1 to the inflammatory response, its role in macrophage biological functions remains largely unexplored. Definitive studies of Aif-1 loss-of-function have not been reported; here we present an analysis of aif-1 inactivation by gene targeting in mice on blood cell populations, macrophage function, and the pathogenesis of atherosclerosis in a hyperlipidemic apoE-/- model. Mice lacking Aif-1 appear grossly normal, breed well, and have normal leukocyte profiles in both peripheral blood and lymphoid tissues, but their macrophages show decreased migration, phagocytosis, and survival after oxidative stress. While these functional impairments do not prevent mice from developing atherosclerosis, lesions from aif-1-/- ;apoE-/- mice show more necrosis than those from apoE-/- mice. Necrotic cores are composed of unphagocytosed dead cells and debris within atherosclerotic lesions, these are hallmarks of unstable plaques prone to rupture. Our studies also revealed that Aif-1 deficient mice are protected from developing high fat diet induced obesity. Mice lacking Aif-1 accumulate less visceral and subcutaneous fat than wt mice and are more glucose tolerant and insulin sensitive. Using the 3T3-L1 adipocyte cell line, we identified a shorter Aif-1 splice variant in adipocytes, highly homologous to the macrophage Aif-1. Thus, these findings point to an important functional role for Aif-1 in opposing atherosclerotic lesion destabilization by supporting macrophage survival and promoting the in vivo clearance of cellular and other debris in the development of the atherosclerotic necrotic core and identify a previously unreported Aif-1 splice variant that may be exclusively expressed in adipose tissue to regulate the development of high fat diet induced obesity.