Origin, differentiation and plasticity
After a decade of studies, the role of monocyte/macrophage functions was found to be dependent on the state of macrophage differentiation [5, 6]. Re-established concepts in macrophage biology have led to a new understanding of the origins, biology and phenotypes of lung macrophages. Mounting evidence in recent years has revealed the plasticity of macrophages and has indicated that macrophages may arise through differentiation through a pre-cursor cell type (Fig. 1). Macrophages originate during the prenatal stage from the yolk sac and fetal liver, and during the postnatal stage from the bone marrow [7, 8]. Tissue-resident macrophages were shown to arise from embryonic progenitors that seed in the intestine and mature locally before and shortly after birth. They are maintained by proliferative self-renewal mechanisms throughout life, largely independent of replenishment by blood monocytes in the steady state [9-11]. However, during inflammation, blood monocytes are recruited from the bone marrow to inflamed intestinal tissues where they differentiate into macrophage populations. These cells with distinct ontogenetic and proliferative histories are exposed to regional signals in inflamed intestinal tissue, but their distinct responses and further programming are largely unexplored.
Tissue-resident macrophages originate from both the yolk sac and fetal liver in the pre-natal stage. During inflammation/injury, an additional subset of macrophages originate from the bone marrow and migrate into inflamed intestinal tissues [12]. These infiltrated macrophages require predominantly CCL2/CCR2 axis, which was evidenced in CCR2-KO mice that showed deficit monocyte infiltration into gut tissues [13, 14]. These infiltrated macrophages are exposed to the micro-environmental stimuli and correspondingly adapt their functional repertoire, and differentiate into tissue resident macrophages, if these are depleted, by inflammatory stimuli or by infection [15].
In mice, two blood monocyte subsets have been distinguished based on the differential expression of Ly6C and CX3CR1 [16]. Monocytes that express high Ly6C levels, intermediate CX3CR1levels and high CCR2 levels are termed Ly6Chi monocytes. They are also known as inflammatory monocytes due to their ability to migrate to sites of inflammation and produce pro-inflammatory cytokines during infection or tissue damage [16] [17]. The second major monocyte subset in mice characterized by low Ly6C expression, high CX3CR1expression and low CCR2expression is termed the Ly6Clowsubset, which patrols for monocytes, acting to maintain capillary integrity [18]. After extravasation, Ly6Chi monocytes differentiate into macrophages and monocyte-derived dendritic cells (Mo-DCs). Despite resident macrophages longevity and self-renewing property during homeostasis [19], infiltrated macrophages (CD11clowCD11bhi) from circulating blood Ly6Chi monocytes can complement the prenatally established macrophage compartment, especially under severe inflammatory conditions such as irradiation and infection that cause severe depletion of the resident macrophage population [20]. During later stages of injury long-lived self-renewing resident macrophages can also help in replenishing the resident pool. Thus, resident macrophages may have a chimeric origin, being derived from both yolk sac/fetal liver as well as from bone marrow monocytes,[21, 22] [23]. In addition, the distinct functions of resident and recruited macrophages suggests these were well classified based on their origins [24]. Moreover, several experiments as far back as the early 1970s established that the influx of macrophages plays a crucial role in tissue repair [25, 26]. Peripheral blood monocytes can also replenish intestinal macrophages through mechanisms dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) and CSF-1 signaling in a stimulus-specific manner [27]. Later, these macrophage subsets were classified as alternatively activated macrophages [28], which were found to be involved in development, repair, and tissue homeostasis processes [29].
However, gut-resident macrophages do not fit readily into this ‘M1-M2 paradigm’, having some of hallmarks of both M1 and M2 macrophages [28]. For instance, they express high levels of MHCII and produce TNFα constitutively, features normally associated with M1 or ‘classically activated’ macrophages. However, they also express CD206, CD163, and produce interleukin-10 (IL-10), features associated with M2 or M2-like macrophages [2]. However, they fail to express arginase, which is a key feature of M2 macrophages. Thus, like most tissue macrophages in vivo, those resident in the gut wall adapt to their local environment in complex and specific ways that may not be reflected by the rigid classification of the M1-M2 paradigm.
Figure 1. Macrophage origin, differentiation and plasticity