S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease

Abstract

Amplification of innate immune responses by endogenous danger-associated molecular patterns (DAMPs) promotes inflammation. The involvement of S100A8 and S100A9, DAMPs belonging to the S100 calgranulin family, in the pathogenesis of cardiovascular disease is attracting an increasing amount of interest. S100A8 and S100A9 (also termed MRP8 and MRP14) preferentially form the S100A8/A9 heterodimer (MRP8/14 or calprotectin) and are constitutively expressed in myeloid cells. The levels of circulating S100A8/A9 in humans strongly correlate to blood neutrophil counts and are increased by traditional cardiovascular risk factors such as smoking, obesity, hyperglycemia, and dyslipidemia. S100A8/A9 is an endogenous ligand of toll-like receptor 4 (TLR4) and of the receptor for advanced glycation end products (RAGE) and has been shown to promote atherogenesis in mice. In humans, S100A8/A9 correlates with the extent of coronary and carotid atherosclerosis and with a vulnerable plaque phenotype. S100A8/A9 is locally released following myocardial infarction and amplifies the inflammatory responses associated with myocardial ischemia/reperfusion injury. Elevated plasma levels of S100A8/A9 are associated with increased risk of future coronary events in healthy individuals and in myocardial infarction survivors. Thus, S100A8/A9 might represent a useful biomarker and therapeutic target in cardiovascular disease. Importantly, S100A8/A9 blockers have been developed and are approved for clinical testing.

Figure 1

Overview of the interplay between S100A8/A9, traditional CV risk factors, circulating phagocytes, and atherogenesis. Smoking, hyperlipidemia, hyperglycemia, and obesity induce elevated S100A8/A9 production either directly or indirectly by stimulating neutrophilia and monocytosis. S100A8/A9 enhances phagocyte production in the bone marrow and facilitates their recruitment into the vascular wall through endothelial activation and increased Mac-1 expression and affinity. These effects are primarily mediated by RAGE and accelerated by hyperglycemia. In the vascular wall, S100A8/A9 binding to TLR4 triggers phagocyte activation and secretion of inflammatory cytokines, further contributing to phagocyte recruitment and accelerated atherogenesis. M-CSF: macrophage colony stimulating factor; GM-CSF: granulocyte-macrophage colony stimulating factor; RAGE: receptor for advanced glycation end products; TLR4: toll-like receptor 4.