Monocytes are short-lived innate immune cells that originate in the bone marrow. In the steady state, monocytes circulate in the blood and survey tissues, but, in response to infection and injury, monocytes rapidly accumulate in tissue where they can give rise to macrophages. In mice and humans, monocytes can be divided into subsets that are identified by surface marker combinations and specific functions. So-called non-classical monocytes patrol the vasculature and support tissue homeostasis, while classical monocytes pursue inflammatory tasks. 1 The classical monocyte subset expresses high levels of the chemokine receptor CCR2, which is also expressed by myeloid progenitors and a haematopoietic stem cell subset, 2 among other cells. In the manuscript published in this issue of the journal, Bernelot Moens and coworkers describe an interesting correlation between monocyte CCR2 expression and LDL-cholesterol in humans. 3 Hypercholesterolaemia is a well-understood risk factor for atherosclerosis. The proatherogenic effects arise when cholesterol accumulates in the subintima, which can lead to evolution of atherosclerotic plaques. The critical role lipids play in atherosclerosis has motivated work leading to the development of statins and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors that efficiently lower blood LDL-cholesterol levels. However, even patients with wellcontrolled LDL-cholesterol have a residual risk for ischaemic events, which might be ascribed to inflammation. 4 Monocytes and monocyte-derived macrophages are protagonists of inflammation in atherosclerosis, and have been linked to hypercholesterolaemia. Preclinical work established that inflammatory monocytes increase in mice with hypercholesterolaemia, 5, 6 that the cells’ production occurs not only in bone marrow but also in extramedullary sites such as the spleen, 7 and that disrupted reverse cholesterol transport leads to increased monocyte production. 8

Monocytes rely on the chemokine receptor CCR2 to migrate to inflammatory sites (Figure 1). First, the cells react to CCR2’s cognate receptor, the chemokine MCP-1 (monocyte chemoattractant protein 1), to depart into bone marrow sinusoids, and thus leave haematopoietic tissue. This mechanism was first described in mice exposed to lipopolysaccharide, a component of the bacterial wall. 9 Once in circulation, inflammatory monocytes continue to rely on CCR2 for recruitment into plaques 10, 11 and ischaemic tissue. 12 Interestingly, even heterozygous CCR2 deficiency impairs monocyte migration towards MCP-1, indicating that smaller fluctuations of CCR2 may be functionally relevant. 13 The importance of CCR2 in ischaemic heart disease is illustrated by the profound reduction of atherosclerosis and ischaemic injury in mice with genetic CCR2 deletion. 10, 12 Therapeutic targeting of CCR2 likewise greatly reduced monocyte migration to inflamed atherosclerotic plaque and myocardium. 14 Bernelot Moens et al. examined CCR2 expression in 22 patients with familiar hypercholesterolaemia (FH) treated with a PCSK9 inhibitor, a recently established drug class that efficiently lowers LDL-cholesterol via increasing availability of hepatocyte LDL receptors, thus enhancing liver clearance of LDL-cholesterol from blood. The authors examined monocyte phenotypes before and after a 24-week treatment course, a design that enables conclusions about a relationship of LDL-cholesterol to changes in monocyte phenotype. C-reactive protein blood levels were not altered by the treatment, indicating that PCSK9 inhibitor action, as expected, was focused on cholesterol metabolism. The patient cohort was also …