The Link Between Dysregulated Immunometabolism and Vascular Damage: Implications for the Development of Atherosclerosis in Systemic Lupus Erythematosus and Other Rheumatic Diseases

Abstract

A bimodal pattern of mortality in Systemic Lupus Erythematosus (SLE) exists. Early-stage deaths are predominantly caused by infection, while later-stage deaths are caused mainly by atherosclerotic disease. Further, while SLE-related mortality has reduced considerably in recent years, cardiovascular events remain one of the leading causes of death in people with SLE. Accelerated atherosclerosis in SLE is attributed both to an increase in traditional cardiovascular risk factors and the inflammatory effects of SLE itself. Many of these changes occur within the microenvironment of the vascular-immune interface, the site of atherosclerotic plaque development. Here, an intimate interaction between endothelial cells, vascular smooth muscle cells, and immune cells, dictates physiological versus pathological responses to a chronic type 1 interferon environment. Low-density neutrophils (LDNs) have also been implicated in eliciting vasculature-damaging effects at such lesion sites. These changes are thought to be governed by dysfunctional metabolism of immune cells in this niche due, at least in part, to the chronic induction of type 1 interferons. Understanding of these novel pathophysiological mechanisms and metabolic pathways may unveil potential innovative pharmacological targets and therapeutic opportunities for atherosclerosis, as well as shed light on the development of premature atherosclerosis in SLE patients who develop cardiovascular events.