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Macrophage2015; 2: e709.doi: 10.14800/Macrophage.709; © 2015 by Indira Guha, et al.
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REVIEW
Macrophage as a mediator of immune response: Sustenance of
immune homeostasis
Indira Guha1, Debdut Naskar2, Malini Sen1
1
Division of Cancer Biology and Inflammatory Disorder, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata-700032,
India
2
Kingston College of Science, Barasat, Kolkata-700126, India
Correspondence: Malini Sen
E-mail: [email protected] or [email protected]
Received:March 12, 2015
Published online:April 07, 2015
Macrophages have evolved as a key player in our immune system. As macrophages remain groomed to combat
invasions by pathogens they also exhibit distinct polarized (M1/M2) states while adapting to the local
environmental milieu. Detailed molecular mechanisms governing the prevalence of the usual steady state as well
as altered (M1/M2) homeostasis programs under normal and pathogenic conditions remain to be deciphered. In
this review, we have discussed the significance of immune homeostasis in macrophages and the involvement of
Wnt – Frizzled signalling therein. Overall this review throws light upon some important questions related to the
immune homeostasis scheme, answers to which will offer new insight in the field of immunology.
To cite this article: Indira Guha, et al. Macrophage as a mediator of immune response: Sustenance of immune
homeostasis.Macrophage 2015;2: e709. doi: 10.14800/ Macrophage.709.
Introduction
Among the myriad of specialized cells that orchestrate our
immune system, macrophages are one of the crucial members
responsible for fighting against infection by pathogens [1].
Monocytes, which originate from their bone marrow resident
myeloid precursor, give rise to macrophages [2-3]. When
circulating monocytes infiltrate tissues they get transformed
into macrophages. The tissue macrophages not only
eliminate encountered pathogens through phagocytosis but
also process and present the foreign antigens via MHC
molecules to lymphocytes causing lymphocyte activation [4].
Phagocytosis by macrophages is regulated by cytoskeletal
modifications which are coordinated at least partly by Wnt –
Frizzled signalling [5]. Not all tissue macrophages however,
originate from monocytes [6-9], and although some origins
have been specified the precise paths leading to the mature
cell types remain largely uncharacterized.
The various kinds of macrophages differing in both
phenotype as well as function may arise from different cell
differentiation pathways and environmental inputs obtained
from neighbouring cells [10]. While obliterating invading
pathogens and other foreign materials from tissues,
macrophages usher in several modes of signalling that are
totally dependent on the existing framework. Cytokines in
the milieu and the nature of pathogenic stimuli influence the
mode of activation of tissue macrophages [11-13]. While
pro-inflammatory cytokine secretion is associated with
persistence of macrophages in the M1 mode (classical
activation mode), anti-inflammatory cytokines are associated
with an alternative mode of activation, namely the M2 mode
[14-15]
. The M1 macrophages promote antigen presentation
associated with Th1 (T helper) cell activation, facilitating
inflammation. M2 macrophages on the other hand support
Th2 cell activation, which while being an inherent
component of allergic responses, is also involved in wound
healing and repair of tissue often associated with resolution
of inflammation [12, 14-16]. Apart from M1 and M2, a third
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Figure 1. Steady State Homeostasis and Macrophage Polarization. Circulating monocytes after
migrating to the tissues differentiate into macrophages upon encountering pathogens. Tissue macrophages
can either undergo Classical Activation thereby promoting the M1 type or Alternative Activation which
promotes the M2 type. Which pathway will be adopted by the tissue macrophages is determined by the
cytokine secretion profile. An equilibrium may exist between the M1 and M2 macrophages.
category of macrophages that demand attention are the
Tumor Associated macrophages (TAMs). Though TAMs
resemble M2 macrophages to a certain extent, their
transcriptional profile is quite different from that of M2 [10].
The exact molecular mechanisms directing the divergence
and polarization of macrophages to the specific subtypes
have not been clearly dissected. Whether the M1 subtype
evolves into M2 with the nature and duration of the prevalent
infections remains an open question. More so, details of the
mechanism of immune homeostasis that keep macrophages
groomed to react to local stimuli during the steady state
(basal activation) as well as polarized state (differential
modes of activation) also remain unsettled. This review
focuses on the intrinsic functions of macrophages in the
context of some recent developments as well as pending
questions with respect to mechanisms of immune
homeostasis.
Macrophages exhibit diverse functions: the driving gear
therein?
Macrophages reside in almost all types of tissues present
in the body. Their function is dictated by the tissue type they
reside in. Macrophages present in the brain and spinal cord,
known as microglia uphold an active immune defence
scheme in the central nervous system.
Alveolar
macrophages likewise clear the air spaces from infectious,
toxic or allergic particles that cross the protective barriers of
our respiratory tract. Similarly, peritoneal macrophages
present in the peritoneum and Kupffer cells of the liver act to
confront infectious agents encountered effectively. Although
a major portion of the tissue macrophages is derived from
blood monocytes [17], tissue macrophages can also be
generated independently. Macrophages of the central nervous
system (CNS) for example, are derived from the yolk-sac,
independent of monocytes [18]. Recent studies on
“fate-mapping” in mice also indicate lack of involvement of
monocytes in the survival and maintenance of specific
populations of tissue macrophages [19]. It is only natural to
assume that there will be a certain level of distinctness in the
combat mechanism of each macrophage type as different
combat mechanisms may arise from different modes of
pathogenic recognition, endocytic entry and subsequent
signal transduction. Such a scenario is in agreement with the
diverse origin of macrophages and their diverse range of
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Figure 2. Steady State Signalling Sustains Innate Immune Response Macrophages. Upon interaction of
Wnt5a with its cognate receptor Fz5, basal Dvl activation ensues which further activates Rac1. Rac1 can
activate IKK2β either directly or via PI3K via a pathway which is still not very clear. Activated IKK2β causes
proteosomal degradation of IκB rendering p65 free to translocate to the nucleus and cause transcription of
responsive genes. This leads to expression of CD14, Bcl2, IFN-ϒ and IFN-β all of which promote innate
immune response. CD14 interacts with TLR4 leading to bacterial clearance via phagosome formation which
is accompanied by increase in proinflammatory cytokine secretion. CD14 can also interact with TLR6/TLR7
thereby activating IRF-3 and causing antiviral response.
functions.
A crucial aspect in the immune response to infections is
the adaptation of tissue macrophages to the infectious agents
inhabiting the local milieu. Macrophages display the inherent
ability to ingest and inactivate infectious agents through
phagocytosis, which correlates with a trend towards the M1
subtype and the secretion of proinflammatory cytokines like
TNF-α [10, 20-23]. Thus while effective phagocytosis during the
innate immune response by macrophages facilitates clearance
of infections, an excess of inflammatory cytokines generated
during uncontrolled phagocytosis may lead to the
perpetuation of inflammation and tissue injuries, as depicted
in figure 1 [10, 21, 24-25]. Pathogenic conditions linked with
chronic inflammation may lead to sepsis like conditions
[26-29]
. Interestingly, progression of sepsis apart from giving
rise to M1 type macrophages also engages M2 polarized
macrophages [30] with an alternative state of activation in
anti-inflammatory
cytokine
secretion.
These
anti-inflammatory cytokines for example, TGF-β and IL10,
while promoting resolution of inflammation and tissue repair,
also endorse immunosuppression [31-35]. Both suppression and
activation of immune responses furthermore, involve
interplay of macrophages and T cells (both CD4 and CD8) in
the context of differential modes of antigen presentation, a
feature of the adaptive immune response program. Th1 and
Th2 cells accordingly modulate cytokine secretion and
signalling networks that fine-tune immune activation and/or
immune suppression [16, 36-39]. Yet another feature embedded
within the macrophage mediated immune response program
is efferocytosis [40], the process by which macrophages
engulf and eliminate apoptotic cells that may be infected
from sites of inflammation. Failure to execute proper and
effective efferocytosis may lead to the accumulation of
unwanted necrotic material [40]. Efferocytosis is receptor
mediated [41], Rho and Rac1 activity coordinating the
engulfment of the apoptotic cells. This ensures the formation
of a spacious phagosome, termed efferosome, which
surrounds the newly engulfed apoptotic cells and eventually
kills them.
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Figure 3.Canonical and Noncanonical Wnt Signalling. In the canonical pathway, Wnt interacts
with its receptor, Frizzled which activates Dishevelled (Dvl). This inhibits GSK3β rendering β-catenin
free to translocate to nucleus and interact with TCF/LEF thus leading to transcription of target genes.
The non canonical pathway can work without β-catenin. It involves either Rac1 mediated or calcium
response mediated signalling. Activated Dvl can activate Rac1 which further activates JNK leading to
the translocation of phosphorylated Jun to the nucleus. Dvl mediated Rac1 activation can also
activate IKKβ leading to p65 nuclear translocation where it causes transcription of target genes. On
the other hand, Dvl can also activate PLC which via conversion of phospholipids to inositol
trisphosphate generates elevated levels of Ca2+. This activates Calceneurin which then causes
dephosphorylation of NFAT causing its nuclear translocation.
Macrophages remain groomed to act according to the local
environment. But what is the mechanism behind such a
response by the macrophages? How is immune homeostasis
sustained in its different essences for both the M1 and M2
macrophages? How in the first place does the innate immune
system equip macrophages with the potential to circumvent
infection? Could a steady state basal signalling serve to keep
the macrophage guarded to confront infection? Macrophage
identity is maintained at the transcriptional level by the
transcription factor PU.1, which activates transcription of
some crucial genes encoding essential macrophage regulators
by influencing the functions of histone modifying enzymes [6,
10]
. In a healthy living system macrophage defence programs
are maintained by a steady state homeostasis that may
involve specific signaling pathways. Upon pathogen
encounter, these macrophages may differentiate into a
particular polarized phenotype i.e. either M1 or M2
depending on the existing cytokine secretion profile.
Transition from the M1 phenotype to the M2 phenotype may
occur in cases of chronic infection and sepsis, but the
molecular mechanism of such a transition remains unknown.
Whether the reverse M2 – M1 transition is possible in vivo is
also not clear. Although existing literature suggests the
prevalence of M1/M2 macrophages with an altered state of
homeostasis under pathogenic conditions, how such altered
steady states are generated as well as maintained in vivo
remains a major question. Does the switch to such
transformed steady states lie in the transcription profile of the
macrophages? Fig1 explains the different levels of immune
homeostasis in macrophages and upholds the unanswered
questions. Exploring the answers to such questions will be
indeed challenging.
Potential involvement of a steady state signalling in
sustaining innate immune response in macrophages
Although macrophages have long been recognized for
displaying innate immune response to bacteria and virus [32,
41-43]
, not much is known about the steady state signalling
that sustains such in-built innate immune defence programs.
We have recently demonstrated that NF-κB, a transcription
factor functioning at the core of our immune system remains
activated at a basal level in macrophages in the steady state.
A low level of NF-κB (p65) is found to be present in the
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nucleus of macrophages in the absence of activating stimuli
[44]
. Several other findings support our data [45]. Interestingly
the low level of constitutive p65 activity in macrophages has
been linked to steady state levels of both CD14 and IFN-β,
which help sustain host protective immune response to
bacteria/LPS and virus. We discovered that a steady state
level of Wnt5a signalling is accountable for the observed
constitutive NF-κB activity [44].This basal NF-κB activity
leads to the expression of CD14 / IFNβ, the promoter
sequence of which at the genome level contains p65 binding
elements [44] (Figure 2). Such steady state signaling can
coordinate with other aspects of macrophage functions as
explained in Figure 2 [44, 46-49].
Wnt5a belongs to a large family of Wnt glycoproteins
comprising about 18 members. Wnts (ligands) transmit
signal upon binding to seven transmembrane span receptors
termed frizzled that may operate in complex with LRP5/6
and/or ROR at the cell membrane during signal transduction
[5, 44, 50-53]
. Frizzled-5 happens to be a putative receptor for
Wnt5a. It should, however, be noted that although modified
versions of selective Wnt-Frizzled complex structures have
been solved [52, 54], none of the ligand-receptor complexes
have been truly biochemically characterized in their
physiological contexts. Wnt signalling classically is divided
into two different modes in the context of the transcriptional
co activator β-catenin – the canonical mode, which is usually
dependent on β-catenin and the non-canonical mode, which
may operate without β-catenin [51, 53]. In the canonical mode
of the Wnt pathway, the Wnt-LRP5/6-Frizzled complex in
combination with the cytoplasmic adaptor protein
Dishevelled (Dvl) inactivates the constitutive kinase activity
of GSK3-β, which in the absence of the Wnt stimulus would
phosphorylate β-catenin driving it towards proteosome
mediated degradation. Lack of phosphorylation results in the
accumulation of the stable β-catenin in the cytoplasm causing
it to translocate to the nucleus thus activating transcription
factors of the Tcf/Lef family to initiate target gene
expression [24, 52-53, 55-56] (Figure 3). In the non-canonical
mode of Wnt signalling of which Wnt5a is a representative,
Wnt5a-Frizzled-ROR or Wnt5a-Frizzled initiated signalling
alters the activity of Rho/Rac family GTPases through
differential activation of Dvl [53, 57]. The subsequent
activation of transcription factors such as JNK (AP1), NFAT
and NF-κB through complex signalling networks is usually
independent of nuclear translocation of β-catenin [44, 47, 53,
58-60]
. Another wing of non canonical Wnt signalling is
represented by the Wnt-Calcium (Ca2+) pathway which often
modulates β-catenin mediated signalling in order to sustain
its own effects [58, 61]. This pathway may be exhibited by the
Wnt5a-Frizzled2 complex, which activates Phospholipase C
(PLC) causing cleavage of membrane phospholipids to
inositol trisphosphate (Insp3) and DAG. DAG activates
several isoforms of Protein kinase C (PKC) [62]. InsP3 upon
binding to its cognate receptor in the endoplasmic reticulum
leads to a surge in cytoplasmic Ca2+ levels. High calcium
levels activate the calmodulin binding phosphatase
calceneurin, which dephosphorylates NFAT thus priming it
for transcriptional activation [63]. DAG primed PKC on the
other hand promotes activation of AP1. Such Wnt5a – Fz2
– phospholipid mediated activation of an API – NFAT
combination can lead to expression of several target genes [64]
(Figure 3). It will be interesting to see if Wnt5a-Fz2
mediated signalling sustains a steady state activation of
NFAT in macrophages thus contributing to the prevalence of
innate immune response programs. Wnt5a-Frizzled2
signalling furthermore causes β-catenin dependent
transcription, this being in compliance with the concept that
actually it is the Wnt5a ligand-receptor combination in the
cell type concerned that dictates the specificity of the Wnt5a
mediated signal transduction scheme [53].
In our study on immune homeostasis in macrophages, the
inherent Wnt5a-Frizzled5 signalling sustains a steady state
activation of NF-κB (p65) through Rac1 GTPase activity [44].
It will be interesting to find out how Dvl, which also controls
canonical Wnt signalling, functions with respect to Wnt5a –
Frizzled5 signal transduction pathways to maintain the
steady state activation of NF-κB (p65) in macrophages. The
Wnt5a-Rac1-p65 homeostatic circuitry as documented by us
has the potential to restrain infection at least partially through
CD14 – TLR and IFNβ mediated bacterial and viral
clearance [44, 65-66]. CD14 – TLR and IFNβ responsive
pathways of pathogen recognition and clearance have been
discussed in several excellent review articles [67-70]. The
Wnt5a- NF-κB homeostatic circuit not only contributes to
building the initial platform of macrophage defence against
both bacteria and virus in the steady state, but it is also
necessary for macrophage survival [32, 41, 44, 46] (Figure 2).
Moreover, the Wnt5a-Fz5 signalling scheme allows
phagocytosis by lipid raft clustering concomitant with
Rac1-PI3 kinase and IκB kinase activation which may or
may not be CD14 dependent [5, 44,46] (Figure 2). It needs to be
investigated whether other modes of Wnt signalling also
participate in the sustenance of such steady state of immune
response in macrophages.
Immune homeostasis vs. macrophage polarization:
Involvement of Wnt Signalling?
Macrophage polarization is perhaps a continuous mode of
activation based on the local milieu [71-73]. Just as a steady
state (basal) signalling keeps macrophages groomed to
circumvent infections as part of the innate immune response
program, other homeostatic circuitries may be able to sustain
the differentially polarized states of macrophages under
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various pathogenic conditions as in sepsis [26-27], rheumatoid
arthritis [74], HIV infection [75], asthma [76] and chronic
obstructive pulmonary disease (COPD) [77-80]. While it is true
that transcriptional profiles of M1 vs. M2 macrophages have
been studied and cytokines such as TNF-α / IFN-γ and IL4
help propagate the M1 and M2 type of macrophages
respectively, in vitro, it is not clear at the molecular level
how these macrophages evolve and sustain themselves in our
system in vivo [81-85]. In COPD patients and also in
experimentally induced COPD in mice, presence of both M1
and M2 polarized macrophages are observed [76, 79, 81]. During
the onset of experimental disease in mice, components of
smoke may induce polarization towards the M1 phenotype,
enhancing the release of proinflammatory cytokines like
IL-6, IL-8, IL-1β and TNF-α. With time, the rates of
phagocytosis/ efferocytosis by the prevailing M1 / M2
macrophages may change. In HIV infection, the mature
macrophage can be polarized to both M1 and M2 and this
polarization may be a crucial factor deciding susceptibility to
HIV infection [75]. In Asthma patients, although Th2
activation plays a dominant role in disease progression, there
are some reports indicating a comparable role of both M1
and M2 macrophages in the development and sustenance of
the disease [76].
immune activation and immune suppression [65, 89], would
maintenance of a balance between the M1 and M2 states
through appropriately targeted interventions of Wnt
signalling intermediates under pathogenic conditions be
beneficial? This remains an open question.
Concluding remarks
From the perspective of immune deficiency / immune
suppression and autoimmunity it is important to understand
steady state signalling or the status of immune homeostasis,
especially in macrophages. Defects or modulations in the
basal levels of immune response in macrophages under
different situations may lead to either immune deficient
conditions from lack of pathogen clearance or autoimmunity
from altered macrophage mediated lymphocyte activation.
Autoimmunity could ensue due to transformed regulations at
different stages or levels of macrophage function ranging
from annihilation of infection to wound healing and tissue
repair [1, 3, 28, 74, 90-91]. A detailed knowledge of signalling
pathways that sustain immune homeostasis in macrophages
under normal as well as pathogenic conditions is thus much
needed.
Acknowledgements
In light of the fact that Wnt signalling is a primordial
event in tissue patterning/organization during development
and partakes of cell migration, wound healing and repair, it
may be worthwhile to test the influence of appropriate Wnt
family members in inflammation and its aftermath as
contributed by the M1 and M2 subtypes of macrophages. The
Wnt family comprises several members and it is quite
possible that their effects in terms of sustenance of immune
responses will be varied. Since Wnt5a mediated signals
promote TNF-α production [5, 50, 85], it is quite possible that
Wnt5a maintains sustenance of the M1 subtype through
distinctive homeostatic circuitries depending on the
prevailing stoichiometry of ligand-receptor pairs in the
different cells in context. At the same time it cannot be ruled
out that distinct doses of Wnt5a in combination with LPS
promote a tolerogenic or M2 like effect in macrophages
[86-88]
. Thus different proportions of the same signal may
allow transition from the M1 phenotype to M2 and vice versa
depending on other factors present in the milieu. Perhaps
appropriate harvesting of inflammatory (M1) and wound
healing / immunosuppressive (M2) macrophages and careful
analysis of the Wnt signals that sustain their phenotypes
would throw light on the involvement of Wnt mediated
homeostatic circuits in the maintenance of macrophage
polarization. But, how useful is the prevalence of polarized
macrophages through homeostatic circuits? Since M1 and
M2 subtypes of macrophages are radically separated with
respect to their status of activation, namely inflammation /
The authors acknowledge the Dept. of Biotechnology,
Govt. of India and CSIR-IICB institutional grant for funding.
The authors are grateful to A. Chakraborty, S. Kundu and all
other lab members for critically reviewing this article.
Disclosures
The authors have no conflict of interest.
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