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1078 Part VIII: Monocytes and Macrophages Chapter 68: Production, Distribution, and Activation of Monocytes and Macrophages 1079

Figure 68–4. Heterogeneity of monocytes in blood and the contribution of different subsets to resident and inflammatory macrophages DCs in
tissues. For further details see Ref. 34. (Used with permission of S. Seif, GraphisMedica, 2014.)

nodes. It is not known if the constitutive exit from blood is a stochastic macrophages with an M1 proinflammatory profile migrate to the
process or specific to particular tissues. cardiac tissue and are involved in cardiac remodeling (Chap. 134). 46
Phenotypic heterogeneity of monocyte populations has become a In atherogenesis, there is recruitment of monocytes into the vas-
topic of intense interest, thanks to the availability of surface antigens/ cular wall at sites of turbulent flow. Once within the subendothelial
receptors such as CD14, CD16 (human), and Ly6C (mouse), and anal- tissue, the monocytes differentiate into macrophages and engulf oxi-
ysis of chemokine/receptor expression, especially fractalkine receptor dized low-density lipoprotein accumulated in arteries, leading to foam
34
(CX CR) and CCR2. Figure 68–4 illustrates the subsets and tissue cell formation, atheroma development, and the secretion of profibrotic
3
progeny established by the use of genetically manipulated mice and agents by adjacent vascular smooth muscle cells, resulting in a fibrous
Table 68–1 compares expression of markers to characterize monocyte cap formation. Thus, vascular wall macrophages are key factors in ini-
subsets in mouse and human blood. The relationship of monocyte pre- tiating the atherosclerotic lesion. Moreover, macrophages activate the
cursor subsets that give rise to inflammatory tissue macrophages and coagulation cascade (Chap. 67) inducing thrombus formation and vas-
DCs is better defined than is that of those that give rise to resident cells, cular occlusion.
which turn over more slowly. Current studies aim to elucidate the subset
origin of other recruited populations, for example, in atherosclerosis, Resident Macrophage Populations in Adult Tissues Overview
normal CNS, and tumors, and in response to metabolic, traumatic, or It is important to describe first the nature of those macrophages present
degenerative injury. Conceptually, it is still not clear how stable these throughout the body as resident populations, in the absence of overt
apparently distinct subsets are or whether they represent part of a con- inflammation, before considering the altered monocyte-derived macro-
tinuous phenotypic spectrum, arising by modulation of subpopulations phages recruited to local sites by infectious or sterile inflammatory (e.g.,
rather than irreversible, true differentiation. Separation and microarray metabolic) stimuli. The properties of such elicited macrophages are well
analysis of freshly isolated monocytes will yield further information established and are described in Chap. 67. However the functions of
regarding this question, providing novel markers and diagnostic signa- resident macrophages, especially in different organs, are still mysterious
tures. Removal from an in vivo environment, as well as in vitro artifacts, and are considered in outline here, with further details in Chap. 67.
can profoundly alter the phenotype and function of monocytes in such The use of differentiation antigens such as F4/80 and cd68 (mouse)
studies. Imaging and in situ analysis may enable single-cell direct stud- and CD68 (human) has made it possible to define resident macrophage
47
ies of their fate. populations in mouse tissues, and to compare their anatomic rela-
Monocyte/macrophages have a major role in the development and tionships in the two species (Table 68–2). F4/80 (EMR1), a member
progression of cardiovascular disease. 44,45 In acute myocardial infarction of a family of epidermal growth factor-7 transmembrane (EGF-TM7)

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