Macrophage Heterogeneity Complicates Reversal of Calcification in Cardiovascular Tissues

• Editorials
• atherosclerosis
• cardiovascular disease
• interleukin-4
• macrophages
• osteoclasts

Macrophages are highly heterogeneous cells exhibiting a wide range of protein markers, tissue locations, and functions. Often thought of as host defense cells with phagocytic, innate/adaptive immune system, and proinflammatory roles, macrophages contribute to a variety of tissue functions, including adipose thermogenesis, tissue repair, splenic and hepatic iron recycling, neural synaptic pruning, and cardiac electric conduction. In the current issue of Circulation Research, Chinetti-Gbaguidi et al¹ enhance our understanding of the diverse roles of macrophages in vascular disease by reporting that macrophages near calcified regions of human atherosclerotic lesions display low mineral resorption potential. This study ties macrophage osteoclastogenesis to vascular calcification and identifies disrupted signaling pathways that may help to develop anticalcification therapies.

Article, see p 19

A traditional view proposed mechanisms for macrophage polarization induced by proinflammatory stimuli, such as lipopolysaccharide and interferon-γ (so-called classically activated or M1 macrophages) or anti-inflammatory factors, for example, interleukin 4 (alternatively activated or M2 macrophages). Recent evidence has suggested that macrophage heterogeneity is more multidimensional.² We demonstrated that M1-like human primary macrophages elicited by interferon-γ contain subpopulations, suggesting a more complex pattern of heterogeneity than a traditional theory of macrophage dichotomy.³ This diversity brings complexity to the pathogenesis of vascular disease. In atherosclerotic plaques, macrophages contribute to disease progression by secreting proinflammatory and cytotoxic factors and releasing matrix metalloproteinases resulting in extracellular matrix breakdown and plaque instability.⁴ These phagocytes also have beneficial roles, such as removal of lipoproteins and apoptotic cells and resolution of inflammation. Similarly, the balance of various macrophage functions may promote or inhibit cardiovascular calcification. Cardiovascular calcification is one of the strongest risk factors associated with negative clinical outcomes in cardiovascular disease, …