Differentiation of Circulating Monocytes

Bone marrow gives rise to monocytes (cMoP) that egress via a CCR2-dependent mechanism to the blood. Human monocytes comprise 2-8% of white blood cells and circulate in blood for about 1-3 days. There are 3 subsets of circulating monocytes in humans: (1) classical (CD14++CD16-, known as LyC6+ in mice), (2) nonclassical (CD14+CD16++, known as CD43+ in mice) and (3) intermediate (CD14++CD16+), defined by the Nomenclature Committee of International Union of Immunologic Societies. Different lines of investigation point to a linear differentiation between the subsets, where classical monocytes act as precursors for nonclassical monocytes, with intermediate monocytes as a transient state (reviewed in Coillard and Segura 2019; Rigamonti et al. 2023; Robinson et al. 2021; Guilliams et al. 2018). Classical monocytes represent 80-90% of monocytes and have also been shown to differentiate either into monocyte-derived macrophages (Mo-Mac) or dendritic cells (Mo-DC) after migrating to tissues. Non-classical and intermediate subsets correspond to 5-10% of total circulating monocytes each. The categorization of the 3 monocyte subsets is based on differential expression of the markers CD14 and CD16 (FCGR3A).

The described functions for each one of these monocyte subsets are:

Classical monocytes: phagocytosis, adhesion and migration, and antibacterial response; low pro-inflammatory chemokine production; immune/defense response;

Intermediate monocytes: phagocytosis, antibacterial response, and antigen presentation; pro-inflammatory response;

Non-classical monocytes: weak phagocytosis, patrolling vasculature, migration, antiviral response, antigen presentation; anti-inflammatory response, immune system process, leukocyte migration. Nonclassical monocytes were shown to exhibit patrolling behavior in vivo (clearing dying endothelial cells and protecting vessel health) and react strongly to nucleic acids and viruses.