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doi:10.1038/nature12034
Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional
diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are
anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are
all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted
by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how
macrophages regulate normal physiology and development, and provide several examples of their pathophysiological
roles in disease. We define the hallmarks of macrophages according to the states that they adopt during the
performance of their various roles, taking into account new insights into the diversity of their lineages, identities and
regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic
targets in many human diseases.
challenges from outside. During these homeostatic adaptations, macrophages of different phenotypes can also be recruited from the monocyte
reservoirs of blood, spleen and bone marrow4, and perhaps from resident
tissue progenitors or through local proliferation5,6. Unfortunately, in
many cases these homeostatic and reparative functions can be subverted
by continuous insult, resulting in a causal association of macrophages
with disease states, such as fibrosis, obesity and cancer (Fig. 1). Thus,
macrophages are an incredibly diverse set of cells that constantly shift
their functional state to new metastable states (set points) in response to
changes in tissue physiology or environmental challenges. They should
not even be considered as one cell type but should be subdivided into
different functional subsets according to their different origins.
Macrophage responses to pathogens have been discussed previously2,7,8
and therefore this Review focuses on the homeostatic mechanisms by
which macrophages contribute to physiological and pathophysiological
adaptations in mammals. Here we define the hallmarks of macrophages
that perform particular functions, taking into account new insights into
the diversity of their lineages, identity and regulation. This phenotypic
diversity is essential to understand because macrophages are central to
many disease states and have emerged as important therapeutic targets
in many diseases.
Immunopathogenesis Section, Program in Tissue Immunity and Repair and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
Maryland 20877-8003, USA. 2Cardiovascular Research Institute, Department of Physiology and Medicine, University of California San Francisco, California 94158-9001, USA. 3Medical Research Council
Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. 4Center for the Study of Reproductive Biology and Womens Health, Department of
Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA.
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Normal physiology
Pathology
Microglia,
(neuronal patterning,
fluid balance)
Neurodegeneration
Yolk sac
Fetal liver
IL-34 CSF1
IL-34 CSF1
Bone marrow
FLT3L
DCs
MDP
CDP
Langerhans
cells
CSF1
Ly6c+
Monocyte
Langerhans
Brain
Pancreas Spleen Liver Kidney
cells
microglia
Lung
Atherosclerosis
F4/80hi
Kupffer cells
(lipid metabolism,
toxin removal)
Fibrosis
Branching
morphogenesis
Metabolism;
adipogenesis
Immunity
Ly6c
DCs
F4/80low
tissue
macrophages
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their lineage dependence on Csf1r may indicate that classification
should be updated14. Dendritic cells will not be discussed further in
this Review, but their biology and lineages have been extensively
reviewed recently14.
In their basal state, resident tissue macrophages show great diversity
in their morphologies, transcriptional profiles, anatomical locations and
functional capabilities23. This functional heterogeneity probably results
from the dynamic crosstalk between resident tissue macrophages and
the client cells that they support. To understand this macrophage diversity there must be an understanding of transcriptional regulation. The
most important of these transcription factors is SFPI1 (also known as
PU.1), a member of the ETS family whose loss following targeted mutation results in complete depletion of CD11b1F4/801 macrophages,
including those derived from the yolk sac6. However, Sfpi1 action is
not limited to macrophages as B cells are also severely depleted in these
Sfpi1-null mutant mice. Similarly, other members of the ETS family are
also involved in macrophage differentiation, including Ets2, which positively regulates the Csf1r promoter. In adults, Mafb (also known as
v-Maf) is required for the local proliferation that maintains resident
macrophages4. In the differentiation of osteoclasts, Fos and Mitf are
required24, whereas Gata2 is required for monocyte development but
not for resident macrophage populations25. However, little is known
about the transcriptional control of the differentiation of the diverse
tissue macrophages, such as those in the liver and brain13. Most research
has focused on their functional activation in response to environmental
challenges23, as discussed below. Nevertheless, the recent transcriptional
profiling of resident macrophages has identified many candidate transcription factors, including those that may regulate core macrophageassociated genes such as Mitf (micropthalmia) family members, Tcf3,
Cebpa, Bach1, Creg1 and genes that are unique to subpopulations,
including Gata6 and Spic, whose targeted gene ablation will undoubtedly
define subsets of macrophages and their unique activities1.
Macrophages in development
Metchnikoff proposed that macrophages participate in the maintenance
of tissue integrity and homoeostasis. To do so, macrophages would need
to be able to discriminate self from non-self, sense tissue damage and
recognize invading pathogens, an insight that led to the concept of
innate immunity for which he was awarded the Nobel prize. The inherent properties of macrophages, which include sensing inside from out,
motility throughout the organism, phagocytosis and degradation, were
later sequestered to instruct the acquired immune system as it evolved
to more efficiently deal with changing pathogenic challenges. This
enhanced sophistication of the immune system probably resulted in
the evolution of dendritic cells as specialized mononuclear phagocytes
to interface with the acquired immune system. Indeed, in mammals,
dendritic cells seem to be focused on initiating tissue immune responses,
whereas tissue macrophages seem to be focused on homeostasis and
tissue integrity9.
Emphasis on the immunological and repair aspects of macrophage
function has overshadowed their importance in the development of
many tissues; for example, studies of Csf1op/op mice, which lack many
macrophage populations, have revealed a cluster of developmental
abnormalities19. Most notable among these is the development of osteopetrosis, which is caused by the loss of bone-reabsorbing macrophages
known as osteoclasts. This phenotype, which is also observed in Sfpi1null mice, is axiomatic for the roles of macrophages in development, in
that cell fate decisions are unchanged but the tissue remodelling and
expression of growth factors is lost. Specifically, although bone formation is intact in Csf1- or Spi1-null mice, the bones are not sculpted to
form the cavities in which haematopoiesis commences19. Consequently,
the functional integrity of the bones, in terms of load bearing and haematopoiesis, is compromised. Csf1op/op mice survive to adulthood because of
extra-medullary haematopoiesis in the spleen and liver19, and as mice age,
osteoclastogenesis is rescued by compensatory expression of VEGF and
therefore bone marrow haematopoiesis commences20.
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In the absence of this signalling there are no microglia, and the brains of
these mice have substantial structural defects as they mature16. Both CSF1
and IL-34 are expressed by neurons in a mutually restricted pattern of
expression, and IL-34 is the major factor for microglial differentiation
and viability10,42. The disruption of architecture in the brain of the Csf1rnull mouse, together with well-documented deficiencies in neuronal
processing regulating olfaction and the reproductive axis in the hypothalamus in Csf1-null mice, strongly suggests that microglia are involved
in the development of neuronal circuitry and the maintenance of brain
structure16,19. Indeed, microglia have been shown to promote neuron
viability19, modulate neuronal activity43 and prune synapses during
development44, as well as express a range of neuronal growth and survival
factors, including NGF19. This conjecture is supported by the finding
that hypomorphic mutation in CSF1R in humans is responsible for hereditary diffuse leukoencephalopathy with spheroids that results from loss
of myelin sheaves and axonal destruction45. These trophic activities of
microglia are also consistent with macrophages having roles in neuroprotection after injury, as defined in a variety of models. These effects
include the promotion of survival and proliferation of retinal progenitor
cells, and the regeneration of adult sensory neurons4648. However, caution needs to be exercised in attributing all of the phenotypes observed in
the brains of Csf1r-mutant mice or humans to the loss of microglia, as
Csf1r expression has been reported on neuronal stem cells and their
development in vivo is regulated by CSF1R42. Nevertheless, it seems likely
that microglia have important roles in the development of neuronal
circuitry, though their effects on the proliferation, survival and connectivity of neurons43, through their effects on myelination, or by modulating angiogenesis and fluid balance in the brain16.
The examples given above indicate a few of the roles for macrophages
in normal development and these are likely to expand with further
study. Phenotypically in mice, macrophages are CD11b1, CD681
CSF1R1 F4/801 and phagocytic and their activities are through the
temporal and spatial delivery of developmentally important molecules
such VEGFs and WNTs as well as proteases. These developmental roles
of macrophages are re-capitulated in repair as described below but are
also intimately involved in chronic conditions that lead to pathologies as
well as the development and progression of malignancies.
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Blood
Adipose tissue
TH1
Bacterial and
viral pathogens
Blood
TH1
Increased numbers
of CAMs in obesity
TH1
IFN-
Toll ligands
IL-1, TNF, IL-6
Saturated fatty acids
Ly6c
Mono
JNK
IRF3
MR
NF-B
CAM
Ly6c
CCL2
OPN
Mono
IL-1
TNF
CCR
CCR2
Monocyte
recruitment
IL-1
Adiponectin TNF
IL-6
Ly6c
Mono
CCL2
CCL5
CCL8
Omega-3
fatty acids
Insulin
sensitivity and
nutrient storage
IL-10
CCR
Inflammatory
monocytes
ILC2
Type 2
immunity
Lipolysis
IL-10
IL-4
IL-13
KLF4
PPAR
STAT6
Eos Eos
Eos
Helminths
Adipocyte
IL-10
AAM
IL-10
Treg
Increased numbers of
AAMs in lean adipose tissue
function of tissue parenchymal cells, in this case the white and brown
adipocytes.
beta-cell dysfunction, resulting in impaired insulin secretion and hyperglycaemia in obese mice. Although these reports have elucidated the
pathogenic role of macrophages in beta-cell dysfunction, in the future
it will be important to determine whether macrophages also participate
in the physiological regulation of beta-cell biology as they do during
development and pregnancy19.
Macrophages in disease
When tissues are damaged following infection or injury, inflammatory
monocytes (Ly6c1 in mice) are recruited from the circulation and differentiate into macrophages as they migrate into the affected tissues4.
These recruited macrophages often show a pro-inflammatory phenotype in the early stages of a wound-healing response. They secrete a
variety of inflammatory mediators, including TNF-a, IL-1 and nitric
oxide, which activate anti-microbial defence mechanisms, including
oxidative processes that contribute to the killing of invading organisms7.
They also produce IL-12 and IL-23, which direct the differentiation and
expansion of anti-microbial TH1 and TH17 cells (T helper cells that
express IFN-c and IL-17) that help to drive inflammatory responses
forward3. Although these inflammatory macrophages are initially beneficial because they facilitate the clearance of invading organisms, they
also trigger substantial collateral tissue damage because of the toxic
activity of reactive oxygen and nitrogen species and of TH1 and TH17
cells71. Indeed, if the inflammatory macrophage response is not quickly
controlled, it can become pathogenic and contribute to disease progression,
as is seen in many chronic inflammatory and autoimmune diseases72,73.
To counteract the tissue-damaging potential of the inflammatory
macrophage response, macrophages undergo apoptosis or switch into
an anti-inflammatory or suppressive phenotype that dampens the proinflammatory response while facilitating wound healing7. These regulatory macrophages often produce ligands associated with development,
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such as WNT ligands, that are essential for tissue repair74. It is becoming
increasingly clear that the mechanisms that regulate the transformation of inflammatory macrophages into an anti-inflammatory cell or
suppressive macrophages back into a pro-inflammatory phenotype has
a major impact on the progression and resolution of many chronic
diseases, as discussed below (Fig. 4).
Macrophages in cancer
Tumours are abundantly populated by macrophages3. Although macrophages were originally thought to be part of an anti-tumour response,
clinical and experimental data indicate that in the large majority of cases
macrophages promote tumour initiation, progression and metastasis75.
In response to persistent infections or chronic irritation, macrophages
synthesize inflammatory cytokines, IFN-c, TNF-a and IL-6, which
engage other immune cells to sustain the chronic inflammation that
seems to be causal in tumour initiation and promotion76. The tumourinducing activities are multi-factorial; for example, through the production of inflammatory cytokines, such as IFN-c in skin cancer that is
induced by exposure to ultraviolet light77 and TNF-a in carcinogeninduced cancer, through the generation of a mutagenic environment76,78
or through alterations of the microbiome79. However, once tumours become established they cause differentiation so that the tumour-associated
macrophages (TAMs) change from an immunologically active state to
adopt a trophic immunosuppressive phenotype that promotes tumour
progression and malignancy (they become tumour-educated)75.
In established tumours, TAMs stimulate tumour-cell migration, invasion and intravasation, as well as the angiogenic response required for
tumour growth75,80,81. These events are required for tumour cells to
become metastatic, as they facilitate their escape into the circulatory
or lymphatic system. Evidence from autochthonous models of breast
cancer suggests that the macrophages take on these activities in response
to CSF1, IL-4 and IL-13 encountered in the tumour microenvironment.
For example, IL-4-mediated differentiation80 results in a reciprocal
paracrine dialogue between CSF1 and EGF, synthesized by tumour cells
and TAMs, respectively, that promotes tumour-cell invasion and intravasation in mammary cancer82. In mammary cancers, this loop is initiated by CXCL12 in the polyoma virus middle T (PyMT) model or
Inflammatory
Promote insulin resistance
Tumoricidal, anti-microbial
NOS2
Matrixdegrading
MMPs
TH1
IL-12
IFN-
ROS
NK
Toxin, irritant or
pathogen
TH17
Neu
Neu
Neu
CAMs
IL-1
TNF
Epithelial damage
Wound healing
Pro-fibrotic
IL-25 IL-33 TSLP
Basophil
TH2
TIMP1 TGF-1
MMP12 PDGF
PFMs
TGFR
IL-4 IL-13
Myofibroblast
Fibroblast
IL-1 3R1
Mast
cell
Collagen
deposition
ILC2
Regulatory or suppressive
Eos
AAMs
Obesity and
insulin resistance
ARG1
RELM
IL-10
Suppress anti-microbial immunity
Anti-inflammatory
Treg
Immune complexes
Glucocorticoids
Prostaglandins
Apoptotic cells
CAMs
IL-10
IL-10
Mreg
TH1
TH17
Breg
TH2
TH1
MAMs TIMs
TAMs
IL-10, TGF-
CTL
CAMs
PDL1, ARG1
NK
TEMs
MDSCs
VEGF, WNT
MMPs, cathepsins
Promote malignancy
Tumour progression
Angiogenesis
Tumour cell invasion and intravasation
Metastatic cell seeding and growth
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PROK2)90. Angiogenic macrophages can be recruited to the tumours by
hypoxia88,91 but also by growth factors such as CSF1 and VEGF92.
Tumours have a proclivity to metastasize to particular sites, and this
phenotype is partially defined by macrophages. Data suggest that the
tumour-produced fragments of ECM molecules or exosomes prepare
these sites, known as pre-metastatic niches, to be receptive to the circulating tumour cells through recruitment of myeloid cells characterized
by CD11b and VEGFR1 positivity93,94. These niches are tumour-typedependent and the fate of the tumour cells can be reprogrammed to a
different tissue by the transfer of tumour-conditioned serum to a naive
mouse strain93. These niches are also dependent on coagulation as
this is necessary for recruitment of the myeloid cells that have recently
been more precisely defined as F4/801 monocytes (or F4/801 macrophages)95. At lung metastatic sites, mini-clots form that enable the arrest
of tumour cells95 that then produce CCL2 to recruit CCR21Ly6c1
inflammatory monocytes that rapidly develop into Ly6c metastasisassociated macrophages (MAMs)96. These monocytes and MAMs
promote tumour-cell extravasation, partly through their expression of
VEGF, which induces local vascular permeability. MAMs that are intimately associated with the tumour cells also promote their viability
through clustering of tumour-cell-expressed VECAM1 that interlocks
with the MAM expressed counter receptor integrin a4 (ref. 83). MAMs
also promote subsequent growth of the metastatic cells and, importantly, ablation of these cells after the metastases are established inhibits
metastatic growth75.
In mice, these individual pro-tumoral functions are carried out by
different subpopulations, although they all express canonical markers
such as CD11b, F4/80 and CSF1R75. This view is consistent with recent
profiling of immune cells in various tumour types in mice and humans
that indicates that there are differences in the extent of macrophage
infiltration and in phenotype97. For example, detailed phenotypic profiling in human hepatocellular carcinoma shows various macrophage subtypes defined by specific location that have both pro- and anti-tumoral
properties through their engagement of the acquired immune system,
although overall the balance is tilted towards pro-tumoral functions98.
Transcriptional profiling of TAM subpopulations in mice suggest they
more closely resemble embryonic macrophages than inflammatory ones,
as they have higher expression of developmentally relevant molecules,
such as those of the WNT pathway75. This strongly suggests that the
trophic roles of macrophages found during development, in metabolism
and in the maintenance of homeostasis, are subverted by tumours to
enhance their growth, invasion and complexity. However, transcriptional
control of these different phenotypes is only just being revealed, particularly in in vivo contexts 3. Many studies have analysed macrophage responses to LPS signalling through nuclear factor-kB (NF-kB), but this
results in activated macrophages that are mainly involved in antibacterial responses and are likely to be anti-tumoral23. In contrast, in their
trophic and immunosuppressive functions, TAMs are shaped by IL-10
and IL-4 or IL-13 that signal to STAT3 and STAT6, respectively3,99. The
PARP proteins and KLF4 also co-operate to induce a pattern of gene
expression associated with their tumour-promoting phenotype3. In
macrophages, CSF1R also signals to a wide range of transcriptional factors, including MYC and FOS15. MYC signalling has been shown to be
important for pro-tumoral phenotypes100. CSF1R expression is regulated
in turn by ETS2 transcription factors, and genetic ablation of this factor
in macrophages in PyMT tumours recapitulates the loss of CSF1 in
tumours, as angiogenesis is inhibited and tumour growth decreases101.
To study the interaction of these factors and other regulatory molecules
such as microRNAs and epigenetic controls3 will require sophisticated
genomic analyses that will help to differentiate the regulation of the
multiple subsets23. These functions and other regulatory systems have
been reviewed recently3.
Macrophages in inflammatory disease
Macrophages have important roles in many chronic diseases, including atherosclerosis, asthma, inflammatory bowel disease, rheumatoid
RESEARCH REVIEW
shown to protect mice from Crohns disease by facilitating the clearance
of pathogenic commensal bacteria from the mucosal lining of the bowel115.
Recruited monocytes and resident tissue macrophages are also thought
to maintain homeostasis in the intestine by clearing apoptotic cells
and debris, promoting epithelial repair, antagonizing pro-inflammatory
macrophages, and by producing the suppressive cytokine IL-10, which is
critical for the maintenance of FOXP3 expression in colonic regulatory T
cells (Treg cells)113,115,116. Macrophages also protect rodents from demyelinating diseases of the CNS by promoting T-cell apoptosis and by expressing the anti-inflammatory cytokines TGF-b1 and IL-10. The inhibitory
receptor CD200 (also known as OX2), which is also expressed on antiinflammatory macrophages, has been shown to prevent the onset of
experimental autoimmune encephalomyelitis in mice117. A unique population of monocyte-derived macrophages also reduces inflammation
resulting from spinal cord injury, providing further evidence of a protective role for macrophages in the CNS118. Together, these observations show
how changes in macrophage differentiation in the local environment can
have a decisive role in the pathogenesis of a wide variety of autoimmune
and inflammatory diseases.
Macrophages in fibrosis
Although macrophages phagocytose and clear apoptotic cells as a part of
their normal homeostatic function in tissues, when they encounter
invading organisms or necrotic debris after injury, they become activated by endogenous dangers signals and pathogen-associated molecular patterns. These activated macrophages produce anti-microbial
mediators, like reactive oxygen and nitrogen species and proteinases,
that help to kill invading pathogens and thus assist in the restoration of
tissue homeostasis. However, they also produce a variety of inflammatory cytokines and chemokines such as TNF-a, IL-1, IL-6 and CCL2 that
help to drive inflammatory and anti-microbial responses forward8,72.
This exacerbates tissue injury and in some cases leads to aberrant wound
healing and ultimately fibrosis (scarring) if the response is not adequately controlled, as has been demonstrated by the selective depletion
of macrophages at various stages of the wound-healing response119.
Therefore, in recent years research has focused on elucidating the mechanisms that suppress inflammation and prevent the development of fibrosis. Although most wound-healing responses are self-limiting once the
tissue-damaging irritant is removed, in many chronic fibrotic diseases
the irritant is either unknown or cannot be eliminated easily120. In this
situation, it is crucial that the dominant macrophage population converts from one exhibiting a pro-inflammatory phenotype to one exhibiting anti-inflammatory, suppressive or regulatory characteristics so
that collateral tissue damage is kept at a minimum (Fig. 4). A variety
of mediators and mechanisms have been shown to regulate this conversion, including the cytokines IL-4 and IL-13, Fcc receptor and TLR
signalling, the purine nucleoside adenosine and A2A receptor signalling,
prostaglandins, Treg cells, and B1 B cells120,121. Each of these mediators
has been shown to activate distinct populations of macrophages with
suppressive or regulatory characteristics. These regulatory macrophages express a variety of soluble mediators, signalling intermediates
and cell-surface receptors, including IL-10, arginase 1, IKKa, MMP13,
maresins, CD200, RELMa and PD-L2, which have all been shown to
decrease the magnitude and/or duration of inflammatory responses,
and in some cases to contribute to the resolution of fibrosis7. They
also produce a variety of soluble mediators, including CSF1, insulinlike growth factor 1, and VEGF, that promote wound healing122. Consequently, in addition to promoting fibrosis, macrophages are intimately
involved in the recovery phase of fibrosis by inducing ECM degradation, phagocytizing apoptotic myofibroblasts and cellular debris, and by
dampening the immune response that contributes to tissue injury120.
Therefore, current fibrosis research is focused on characterizing these
regulatory macrophage populations and devising therapeutics strategies
that can exploit their anti-inflammatory, anti-fibrotic and woundhealing properties.
Perspectives
Our understanding of macrophage biology is increasing rapidly, and it is
now understood that they have diverse origins, transcriptional complexity and lability, and are capable of phenotypic switching in accordance with homeostatic demands and in response to insult. Macrophages
are involved in almost every disease and represent attractive therapeutic
targets because their function can be augmented or inhibited to alter
disease outcome. However, for these therapies to be effective it is necessary to understand macrophage diversity and define their phenotypes
according to anatomical location and function, and according to the
regulation of the particular set-points that define the recognizable macrophages, such as microglia, osteoclasts and Kuppffer cells. Indeed, the
recognition of multiple origins (yolk sac, fetal liver, bone marrow) may
result in the conclusion that there is no such thing as a macrophage
but instead, clades of cells that have similar characteristics but different
origins. Their different origins may in fact provide unique opportunities
to target the recruited monocytes and macrophages selectively in the
context of the chronic diseases discussed above, thereby inhibiting the
pathology without disturbing resident macrophages and thereby maintaining normal homeostasis. To define these similarities and differences it
will be necessary to determine proteomes and transcriptomes of particular subtypes; this was recently performed for resident macrophages1. The
field of genomic analysis is advancing rapidly and will provide unique
insights and novel methods to define macrophage types. Furthermore,
macrophage biology in humans is poorly developed because of the technical limitations of obtaining fresh material for fluorescence-associated
cell sorting (FACS) and the over-reliance of functional and genomic
studies on cell lines such as the myelomonocytic leukaemic cell line
THP1 (ref. 123) or the in vitro differentiation of circulating monocytes
by CSF1. Notable differences also exist between human and mouse macrophages; for example, the inability of human macrophages to increase
arginase 1 expression that is an important marker of IL-4-regulated
macrophages in mice3. These differences mean that the binary classifications such as M1 and M2 are inadequate. Human macrophage diversity
has begun to be defined124; several sequencing efforts are in progress and
these will begin to address the essential need to translate mouse biology
into the human context.
Considerable advances in our knowledge of macrophage biology have
been made recently using mouse genetic approaches. For example,
macrophages can be fluorescently labelled by expressing GFP from
the Csf1r promoter, and this is used to identify and, in some cases, record
live images of them using intravital microscopy23,125. Furthermore, the
development of macrophage-restricted Cre recombinasesfor example,
expressed from the LysM or Csf1r promotersand the ability to ablate
macrophages through the expression of the diptheria toxin receptor,
which sensitizes mouse cells to the toxic effect of diptheria toxin119, or
using miRNAs to direct the expression of herpes simplex virus thymidine
kinase in macrophages, have been key to defining the functions of macrophages. Although these systems have provided notable insights into
macrophage function, none of the promoters is uniquely expressed in
macrophages, and they are also expressed in most macrophage types,
thereby making it difficult to discriminate the functions of subclasses
of macrophages. In the future, specific promoters will be developed to
ablate genes in particular subsets, more sophisticated lineage tracing will
make it possible to follow cell fates, and subtype switching will be possible
through photo-activatable flours such as Dendra2 that enable a single
cell, or a few cells, to be tracked125.
Therapeutic targeting of macrophages is now in progress21,23. Most of
the therapies are targeted at pan-macrophage markers such as CSF1R. In
the case of CSF1R reagents, including small molecules and monoclonal
antibodies that inhibit the ligand, ligand binding or tyrosine kinase
activity of the receptor are at various stages of clinical trials for the
treatment of cancer21. Other strategies in fibrosis and cancer have been
to target the recruitment of macrophages, particularly through inhibition of inflammatory monocyte trafficking with anti-CCL2 or -CCR2
antibodies. In one example, the protective effects of recombinant human
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serum amyloid P (also known as pentraxin 2) in idiopathic pulmonary
fibrosis and post-surgical scarring in patients treated for glaucoma are
thought to occur through the reduction of inflammation and fibrosis
resulting from the induction of IL-10 production in regulatory macrophages107. Neutralization of GM-CSF using antibodies is being tested in
phase II trials for multiple sclerosis and rheumatoid arthritis21. In the
future, it seems that it will be possible to exploit the inherent plasticity
of macrophages to adjust their set points to control obesity by downmodulating inflammatory cytokines, to resolve fibrosis by inducing the
differentiation of resolving macrophages, and to treat cancer by converting macrophages from their trophic to an immunologically activated anti-tumoral state.
Received 18 October 2012; accepted 20 February 2013.
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Acknowledgements The authors apologize to colleagues whose papers they were
unable to cite on this occasion. T.A.W. is supported by the intramural research program
of the National Institutes of Allergy and Infectious Diseases (National Institutes of
Health (NIH)). This work was supported by the National Cancer Institute of the NIH
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