The classical definition of monocytes as mononuclear phagocytes found in the circulation that have not entered tissue must be reconsidered. Recent studies have reported cells with a monocytic transcriptional signature present in many tissues and provided evidence that certain populations of monocytes re-enter the circulation after migrating in and out of solid tissue (Becher et al., 2014; Jakubzick et al., 2013; Tamoutounour et al., 2013). Additionally, the spleen hosts a substantial population of monocytes that rapidly mobilize at the onset of inflammation. While under steady-state conditions these cells do not contribute to most tissue macrophage and classical DC populations (with the previously noted exceptions of certain populations of skin and intestinal macrophages), monocytes are rapidly recruited to sites of inflammation to complement the function of resident APC populations. In these settings, monocytes demonstrate a remarkably diverse range of function in host defense and immunoregulation. Upon entry into inflamed tissue, monocyte-derived cells can differentiate into dendritic cells and macrophages, and demonstrate the potential for both inflammatory and regulatory functions. In this context, macrophages may represent a sort of patrolling APC reservoir, recruited to sites where local APC populations are insufficient or unable to meet the immunological demands of the tissue.
The circulating monocyte pool in both mice and humans is primarily composed of two populations: a “classical” monocyte population (CD14+CD16- in humans, Ly6ChiCD115+CD11b+ in mice) that is recruited to inflamed tissue, and a “patrolling” population (CD14loCD16+ in humans, Ly6CloCD115+CD11b+ in mice) that rolls along the endothelium and has been speculated to represent the resident macrophage of the circulatory system. Recently, the presence of an “intermediate” monocyte population in humans has been noted. This population is poorly understood, but early reports suggest that it may contribute to inflammatory pathology during infection and autoimmunity. It is unclear if a homologous subset exists in mice. Transcriptional analysis of classical and patrolling human and mouse monocyte subsets between species have shown strong conservation between the species. One important difference between mice and humans however, is the relative abundance of these populations in the circulation: classical monocytes represent ~95% of the circulating pool in humans, but only about 50% in mice. For the rest of this section, the discussion will focus on mouse monocytes, whose development and function is better characterized.
Monocytes differentiate from a BM-resident Lin-CD115+cKit+Flt3+Ly6Clo progenitor shared with DCs known as the monocyte-macrophage-DC precursor (MDP) (Figure 1) (Auffray et al., 2009). This population differentiates into a proliferating Lin-CD115+cKit+Flt3-Ly6ChiCD11b- population committed to monocyte differentiation known as common monocyte progenitors (cMoP) before maturing into Lin-CD115+cKitLy6ChiCD11b+ mature monocytes. Ly6Chi monocytes exit the BM in a CCR2-dependent fashion and enter the blood, where they circulate with a half-life of less than 24 hours. The absolute number of blood Ly6Chi monocytes follows a circadian rhythm in accordance with the gene Bmal1, with numbers peaking 4 hours after the beginning of the light cycle. However, this oscillation was abolished during infection with Listeria monocytogenes as a result of increased CCL2 levels in the serum, suggesting that inflammatory stimuli can direct Ly6Chi monocyte abundance in the periphery. Increasing evidence suggests that Ly6Chi monocytes differentiate into Ly6Clo monocytes, although whether this differentiation occurs in the circulation or upon re-entry to the BM is still unclear, as there is experimental evidence for both possibilities. The half-life of Ly6Clo monocytes is approximately 2 days, although their lifespan increases substantially after depletion of Ly6Chi monocytes, perhaps indicating that these cells can be longer lived in the absence of replenishment of their niche by new cells differentiated from Ly6Chi cells.
Both Ly6Chi and Ly6Clo monocytes constitutively express CSF-1 receptor (CD115), and their development and homeostasis is dependent on CSF-1 signaling. Ly6Clo monocytes also express high levels of the fractalkine receptor CX3CR1 and depend on this receptor for homeostasis as well; in the absence of this receptor they have a shorter lifespan and display markers of apoptosis. Transcriptional control of monocytes is not yet thoroughly understood. PU.1 is required for their development, and there is increasing evidence that KLF4, c-Maf, and MafB support monocyte fate by inhibiting granulocyte differentiation. Ly6Clo monocytes are absent in mice lacking NR4A1 (Nur77), but whether this transcription factor is important for their differentiation from Ly6Chi monocytes or is required for the survival of Ly6Clo populations is unclear.