Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease

BACKGROUND: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1 alpha (IL-1 alpha) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1 alpha in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD. METHODS: We assessed the expression of IL-1 alpha on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic cardiovascular disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1 alpha in several organ injury models in Il1a(-/-) and Il1b(-/-) mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells. RESULTS: IL-1 alpha is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1 alpha surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic cardiovascular disease events, which underlines the clinical relevance of IL-1 alpha. In mice, IL-1 alpha, but not IL-1 beta, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1 alpha promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1 alpha on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1 alpha surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1 alpha also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1 alpha induces inflammatory injury after experimental AMI, and abrogation of IL-1 alpha prevents the development of CKD in oxalate or adenine-fed mice. CONCLUSIONS: IL-1 alpha represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1 alpha may serve as a novel anti-inflammatory treatment strategy.

Automated summary

The study found that IL-1 alpha is strongly expressed on the surface of monocytes from patients with AMI and CKD, and is associated with a higher risk for atherosclerotic cardiovascular disease events. In experimental mice, IL-1 alpha mediates leukocyte-endothelial adhesion and promotes accumulation of immune cells in inflamed tissue.