Abandoning M1/M2 for a Network Model of Macrophage Function
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The heart and blood vessels of a healthy individual contain resident immune cells, the majority of which are macrophages that have seeded these organs early in the development. In the mouse, ≈10% of noncardiomyocytes are macrophages,1,2 and humans may have comparable numbers.1 After myocardial infarction, macrophage numbers increase in the heart through the combined effects of massive recruitment of bone marrow–derived cells and local self-renewal.1,3 Likewise, in atherosclerosis, the chronic lipid–driven inflammatory disease that is the underlying cause of myocardial infarction, macrophage numbers increase in the vessel wall, again because of recruitment and local proliferation.4 Although many of these insights have been generated in mouse models, compelling evidence from genome-wide association studies have associated innate immunity mediators with myocardial infarction,5 whereas prospective human studies have shown that blood monocyte levels can predict cardiovascular events in patients.6
During the past decade, multiple studies have challenged and, in some cases, dismantled old assumptions about macrophage origins and functions. Many reviews and opinion pieces7–19—some of them our own20–23—have been written on the subject because the various communities interested in macrophage biology seek to contextualize the findings into a coherent narrative. We now know that, in the steady state, arterial24 and cardiac1,25–27 macrophages are mostly independent of monocytes, but in response to an inflammatory trigger, such as myocardial infarction or high-fat diet, monocyte-derived cells accumulate and differentiate to self-renewing macrophages.3,4,28,29 We also know that macrophage function goes far beyond phagocytosis. Because they reside in nearly every organ, macrophages respond and adapt to their local surroundings, and their noncanonical activities reflect their flexibility. From iron recycling in the spleen30,31 and synaptic …