Macrophage death and defective inflammation resolution in atherosclerosis

Abstract

Atherothrombotic vascular disease (ATVD) is the leading cause of death in the industrialized world, and this problem is growing owing to the increase in obesity and insulin resistance worldwide. ATVD develops as a macrophage-dominant maladaptive inflammatory response to subendothelial lipoproteins. A fundamental aspect of this maladaptive inflammatory response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective phagocytic clearance of apoptotic cells and promotion of inflammatory cell egress. The mechanism of failed inflammation resolution in atherosclerosis is not known, but it is likely to involve defective generation or action of anti-inflammatory cytokines (for example, interleukin-10), pro-resolution lipid mediators (for example, lipoxins) and transcription factors (for example, the liver X receptor family) that normally carry out this process. In advanced atherosclerosis, there is continual recruitment of inflammatory monocytes, and the macrophages that differentiate from these monocytes in lesions may favour the classically activated (M1) subtype, which promote inflammation, over the alternatively activated (M2) subtype, which participate in inflammation resolution. Egress of inflammatory macrophages in advanced atherosclerotic lesions is also defective. Macrophage apoptosis coupled with defective clearance of these apoptotic cells (efferocytosis) in advanced atherosclerotic lesions is a particularly important process because it leads to the generation of plaque necrosis, which is a key feature of the types of atherosclerotic lesions that cause ATVD. One key mechanism of macrophage apoptosis in this setting is a pathway in which the endoplasmic reticulum stress pathway known as the unfolded protein response, perhaps in combination with pattern recognition receptor activation, triggers Ca²⁺-dependent apoptosis. The mechanisms of defective efferocytosis in advanced atheroma are not known, but may involve deficiency, dysfunction and/or competitive inhibition of receptors, ligands and other factors involved in apoptotic cell recognition and engulfment. The ability to translate the complex process of plaque progression into an integrated molecular and cellular concept of defective inflammation resolution provides a useful way to understand how atherosclerosis leads to clinical disease and how plaque progression may be prevented by new therapeutic approaches.