Atherosclerosis and interferon-γ: new insights and therapeutic targets

Abstract

Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall. Atherogenesis is accompanied by local production and release of inflammatory mediators, for which the macrophage is a major source. The proinflammatory cytokine, interferon (IFN)-γ derived from T cells, is expressed at high levels in atherosclerotic lesions. IFN-γ is the classic macrophage-activating factor, vital for both innate and adaptive immunity. It primes macrophages to produce chemokines and cytotoxic molecules and induces expression of genes that regulate lipid uptake. IFN-γ is a key trigger for the formation and release of reactive oxygen species. IFN-γ has important effects on endothelial cells, promoting expression of adhesion molecules. Atherogenic effects of IFN-γ have been shown in murine models where exogenous administration enhances atherosclerotic lesion formation while knockout of IFN-γ or its receptor reduces lesion size. IFN-γ signaling is largely mediated by a Janus kinase (JAK) to signal transduction and activator of transcription (STAT)1 cytosolic factor pathway. A clear understanding of IFN-γ effects on atherogenesis should enable development of novel targeted interventions for clinical use in the prevention and treatment of atherosclerosis. This review will discuss the actions of the cytokine IFN-γ and its complex effects on cells involved in atherosclerosis.

Fig. 1

A schematic representation of the IFN-γ signaling pathway. The receptor for IFN-γ consists of two subunits: IFNGR1, the ligand-binding chain and IFNGR2, the signal-transducing chain. Upon interaction of IFN-γ with the ligand-binding chain, it dimerizes with the signal-transducing chain. Ligand-induced receptor clustering activates the Janus kinases JAK1 and JAK2 and phosphorylation of a tyrosine residue on the intracellular domain of IFNGR1. Phospho-STAT1 dimerizes, dissociates from the receptor cytoplasmic domain, and translocates to the nucleus to activate a wide range of IFN-γ-responsive genes. After signaling, the ligand-binding chains are internalized. The chains are then recycled to the cell surface.

Fig. 2

The role of IFN-γ in oxidative-stress progression and initiation of atherosclerosis. IFN-γ is able to upregulate the expression of the superoxide-producing enzyme NADPH oxidase in human monocytes/macrophages, thus inducing ROS production. ROS induces oxidative modification of LDL. Oxidized LDL (oxLDL) is internalized by macrophage scavenger receptors, leading to lipid overload and foam cell formation (FCF). IFN-γ-induced activation of human macrophages increases the concentration of neopterin. Neopterin may act pro-oxidatively and supports LDL oxidation in vitro. IFN-γ stimulates iNOS-mediated elevation of nitric oxide (NO) concentration. Local release of a large amount of NO metabolites leads to production of peroxynitrite (accelerated by neopterin as well). Accumulation of peroxynitrite enhances platelet adhesion and aggregation, promotes lipid peroxidation, and increases vasoconstriction.

Fig. 3

A schematic representation of IFN-γ effects on atherosclerotic lesion formation. IFN-γ, secreted by the infiltrating T lymphocytes and natural killer T cells (NKT) , induces (red arrows) or inhibits (blue arrows) the expression of numerous genes in endothelial cells , macrophages , and SMC . IFN-γ provokes monocyte/lymphocyte recruitment and infiltration into the subendothelium by induction of MCP-1, M-CSF, and release of adhesion molecules such as ICAM-1, VCAM-1, and P-selectin. IFN-γ promotes foam cell formation by increasing the uptake of modified LDL (mLDL ) by scavenger receptors, like CD36, SRA1, and CXCL16, and reducing cholesterol efflux (ABCA1). IFN-γ-induced release of MMPs enables SMC to migrate through tissue by degrading extracellular matrix. Mature SMC retain remarkable plasticity, become macrophage-like and contribute to the foam cell population of the intima. MMPs are proteolytic enzymes that can weaken and disrupt plaque structure, including the fibrous cap.