Figure 3.

Development and features of murine and human monocyte subsets. Monocyte development from a common myeloid progenitor (CMP) occurs in the bone-marrow under the control of M-CSF and IL-34 and increasing lineage commitment. A macrophage dendritic progenitor (MDP) gives rise to Ly6c^hi monocytes and probably also to Ly6c^lo monocytes. Bone-marrow egress is directed by CCR2, maybe also by other pathways such as CXCR4/CXCL12 (not depicted). Peripheral Ly6c^hi can shuttle back to the bone-marrow and possibly transdifferentiate into Ly6c^lo monocytes, a process that might also occur in the periphery (e.g., in the spleen). Murine monocyte subsets constantly express F4/80 and CD11b. Classical Ly6c^hi are characterized by high expression of CCR2 but only moderate levels of the fractalkine receptor CX₃CR1. Furthermore, they express several scavenger receptors (e.g., CD32), selectin ligand CD62L, and the integrin VLA-2. Ly6c^hi monocytes have a proinflammatory profile since they secrete inflammatory cytokines, migrate into inflamed tissue and give rise to inflammatory macrophages (sharing qualities with classical M1 macrophages), and DC subsets. Ly6c^lo are less abundant in the periphery and express high CX₃CR1, CD86, and LFA-1 whereas CCR2 is almost absent. They patrol blood vessels by crawling across endothelium. During inflammation they can rapidly or protracted enter tissue and presumably develop into macrophages with a rather anti-inflammatory phenotype eliciting wound repair (reminiscent of M2 macrophages). In homeostasis they are currently designated as precursor cells of local macrophages and dendritic cells. Importantly, Ly6C^hi derived macrophages can very likely also acquire anti-inflammatory phenotypes in peripheral tissues such as the liver. Intermediate Ly6c^int are not depicted here. FACS dot plot in the right upper corner illustrates characteristic distribution of human monocyte subsets. CCR2 high expressing CD14⁺⁺CD16⁻ monocytes are termed classical monocytes, representing the vast majority of circulating monocytes. Despite phenotypic homology to murine inflammatory Ly6c^hi monocytes they release immune suppressive IL-10 upon LPS stimulation. In turn, intermediate and non-classical monocytes that are defined by the expression of CD16, display moderate to high CX₃CR1 and varying density of CD14 and are far less abundant, but release various inflammatory cytokines after challenge with TLR4 and TLR7 agonists. These functions sharply contrast the rather anti-inflammatory phenotype of Ly6c^lo monocytes as their putative murine counterparts. Intermediate monocytes and classical monocytes have a distinct surface protein profile (e.g., CCR5 is almost exclusively expressed on the intermediate subset) though functional differences are not fully defined. Abbreviations: CMP, common myeloid progenitor; GMP, granulocyte myeloid progenitor; IFNg, interferon gamma; LFA-1, lymphocyte function antigen 1; M-CSF, macrophage colony-stimulating factor; MDP, macrophage dendritic cell progenitor; NO, nitric oxide; TipDCs, TNF–iNOS-producing dendritic cells; VLA-2, very late antigen 2.