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