Monocyte Differentiation and Heterogeneity: Inter-Subset and Interindividual Differences

Abstract

The three subsets of human monocytes, classical, intermediate, and nonclassical, show phenotypic heterogeneity, particularly in their expression of CD14 and CD16. This has enabled researchers to delve into the functions of each subset in the steady state as well as in disease. Studies have revealed that monocyte heterogeneity is multi-dimensional. In addition, that their phenotype and function differ between subsets is well established. However, it is becoming evident that heterogeneity also exists within each subset, between health and disease (current or past) states, and even between individuals. This realisation casts long shadows, impacting how we identify and classify the subsets, the functions we assign to them, and how they are examined for alterations in disease. Perhaps the most fascinating is evidence that, even in relative health, interindividual differences in monocyte subsets exist. It is proposed that the individual's microenvironment could cause long-lasting or irreversible changes to monocyte precursors that echo to monocytes and through to their derived macrophages. Here, we will discuss the types of heterogeneity recognised in monocytes, the implications of these for monocyte research, and most importantly, the relevance of this heterogeneity for health and disease.

Keywords: differentiation; heterogeneity; inflammation; lipid; monocyte; monocyte subsets; trained immunity.

Figure 1

Traditional model of monocyte differentiation and mobilisation. Monocytes arise in the bone marrow from the differentiation of multiple levels of precursors. They are then released into the circulation where they differentiate through the three subsets, which can migrate into tissue. HSC: haematopoietic stem cell; MPP: multipotent progenitor; CMP: common myeloid progenitor; CLP: common lymphoid progenitor; MEP: megakaryocyte-erythrocyte progenitor; GMP: granulocyte-macrophage progenitor; MDP: monocyte-dendritic cell progenitor; MP: monocyte progenitor; and cMoP: common monocyte progenitor.

Figure 2

Comparison of gating methods. (a) rectangular gating, (b) trapezoid gating, (c) zebra plot displaying median which allows symmetrical gating of classicals with even distribution of cells around median population.

Figure 3

Marker expression within and between subsets. CD11b is expressed highly by some classical monocytes but is low in others, with a similar picture for the intermediate subset. The figure is reprinted with permission from Patel et al. ‘Monocyte subset recruitment marker profile is inversely associated with blood ApoA1 levels’, Frontiers in Immunology 2021 [14]. Copyright 2021 Patel, Williams, Li, Fletcher, and Medbury.

Figure 4

Variation in CD49d between monocyte subsets for different study individuals. Each line on the graph is representative of the relative CD49d marker expression for one individual. Dark orange lines show study subjects with higher expression of CD49d on all three monocyte subsets than the nonclassical subset of the participants indicated by the blue lines. The remainder of the participants’ data is shown in yellow. C: Classical; I: intermediate and NC: nonclassical. The figure is adapted with permission from Patel et al. ‘Monocyte subset recruitment marker profile is inversely associated with blood ApoA1 levels’, Frontiers in Immunology 2021 [14]. Copyright 2021 Patel, Williams, Li, Fletcher, and Medbury.