Monocyte and macrophage heterogeneity. Monocytes originate in the bone marrow where they develop from hematopoietic stem cells (HSCs) via several differentiation steps and intermediate progenitor stages that pass through the common myeloid progenitor (CMP), the granulocyte/macrophage progenitor (GMP), and the macrophage/DC progenitor (MDP) stages. The MDP gives rise to monocytes, which are released in blood circulation where they remain for 1–3 days. In peripheral blood, circulating monocytes represent ~5–10% of peripheral blood white blood cells (WBCs) and are a highly heterogenic population. Three main subtypes have been described based on the expression of CD14 and CD16 receptors: the classical CD14++CD16, intermediate CD14++CD16+, and nonclassical CD14 low CD16++ monocytes. In general, circulation monocytes are recruited to tissues where they can differentiate into dendritic cells or tissue macrophages (Kupffer cells in the liver; microglial cells in the brain, etc.), replenishing the existing populations. Additional heterogeneity also exists between the macrophages, with two major classes being identified: the classically activated (M1) and the alternatively activated (M2) macrophages. M1 macrophages are developed in response to TNF and IFN as well as in response to microbial products such as LPS, and they produce in turn proinflammatory cytokines including IL-1, IL-23, IL-6, and IL-12. M2 macrophages can develop in response to IL-4 and IL-13 cytokines and play important roles in down-regulation of inflammation and tissue remodelling by releasing IL-10 and IL-1 receptor antagonist (IL-1Ra). They also produce high levels of arginase, fibronectin, and a matrix-associated protein, IG-H3.
