Download Macrophage Polarization at the Crossroad Between HIV

ATVB in Focus
Macrophage Diversity in Health and Disease
Series Editor: Ann Marie Schmidt
Macrophage Polarization at the Crossroad Between HIV-1
Infection and Cancer Development
Massimo Alfano, Francesca Graziano, Luca Genovese, Guido Poli
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Abstract—Mononuclear phagocytes play a fundamental role in the tissue homeostasis and innate defenses against viruses
and other microbial pathogens. In addition, they are likely involved in several steps of cancer development. Circulating
monocytes and tissue macrophages are target cells of viral infections, including human cytomegalovirus, human
herpes virus 8, and the HIV, and alterations of their functional and phenotypic properties are likely involved in many
tissue-degenerative diseases, including atherosclerosis and cancer. Different tissue microenvironments as well as their
pathological alterations can profoundly affect the polarization state of macrophages toward the extreme phenotypes
conventionally termed M1 and M2. Thus, targeting disease-associated macrophages is considered a potential approach
particularly in the context of cancer-associated tumor-associated macrophages, supporting malignant cell growth
and progression toward a metastatic phenotype. Of note is the fact that tumor-associated macrophages isolated from
established tumors display phenotypic and functional features similar to those of in vitro–derived M2-polarized cells.
Concerning HIV-1 infection, viral eradication strategies in the context of combination antiretroviral therapy should also
consider the possibility to deplete, at least transiently, certain mononuclear phagocytes subsets, although the possibility
of distinguishing those that are either infected or pathogenically altered remains a goal of future research. In the present
review, we will focus on the recent literature concerning the role of human macrophage polarization in viral infections
and cancer. (Arterioscler Thromb Vasc Biol. 2013;33:1145-1152.)
Key Words: cancer ◼ HIV ◼ human cytomegalovirus ◼ human herpes virus 8 ◼ M1 ◼ M2
◼ macrophage ◼ polarization
Functional Polarization of
Mononuclear Phagocytes
(IFN-γ), and are potent effector cells enabled to kill cells
infected by intracellular pathogens, including viruses, and
tumor cells; they are also sources of proinflammatory cytokines, such as interleukin (IL)-1β, IL-12, IL-15, IL-18, and
tumor necrosis factor-α, thus participating to the induction
and maintenance of CD4+ T helper cells 1 responses.6,8,9 In
addition, M1-cells secrete factors of the Complement cascade
and express high levels of major histocompatibility complex
class I and class II antigens, thereby enhancing the adaptive
immune response to pathogens or tumors.6
In contrast, IL-4, IL-13, glucocorticoid hormones, IL-10,
and antigen-antibody (Ab) complexes, in combination with
cell stimulation via toll-like receptor, induce M2 functional
polarization of tissue macrophages. This activation state is
characterized by poor production of nitric oxide (NO), reduced
to absent secretion of proinflammatory cytokines coupled with
the enhanced ability to scavenge cellular debris, promotion of
neoangiogenesis, tissue remodeling, and repair. M2-polarized
macrophages have also shown an increased capacity to eliminate
extracellular pathogens, including parasites, and participate in
the switch of the adaptive immune response toward CD4+ Th2
Mononuclear phagocyte (MP) encompass bone marrow precursor cells and peripheral blood monocytes that, after a very
short time (1–2 days), migrate into the different organs and tissues. Under the influence of the different microenvironments,
recently migrated monocytes give rise to a variety of MP subtypes, including mucosal macrophages, dendritic cells, and
tissue-associated Langherans cells of skin, perivascular macrophages, Kupffer cells of liver, and brain microglial cells.1–5
In addition to their peculiar differentiation phenotypes, tissue
macrophages may be activated along 2 main functional pathways.6,7 Proinflammatory stimuli result in classically activated
macrophages or M1-cells, which participate to the clearance of
either infected or transformed cells, however simultaneously
contributing to tissue destruction. Conversely, anti-inflammatory signals induce alternatively activated or M2-macrophages
that will activate cellular programs, promoting tissue regeneration and wound healing.
M1-macrophages are typically induced by microbial products and proinflammatory cytokines, particularly interferon-γ
Received on: January 4, 2013; final version accepted on: March 14, 2013.
From the AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan,
Italy (M.A., F.G., L.G., G.P.); and Università Vita-Salute San Raffaele, School of Medicine, Milan, Italy (F.G., L.G., G.P.).
Correspondence to Guido Poli, P2/P3 Laboratories, DIBIT-1, Via Olgettina n. 58, 20132, Milano, Italy. E-mail [email protected]
© 2013 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
1145
DOI: 10.1161/ATVBAHA.112.300171
1146 Arterioscler Thromb Vasc Biol June 2013
pathways.6 Dominance of M2-polarized macrophages has been
also associated with the suppression of antitumor activities.6
M2-macrophages secrete anti-inflammatory molecules, such as
the IL-1 receptor antagonist (IL-1ra), IL-10, and transforming
growth factor-β, thereby inhibiting the inflammatory burst and
the production of proinflammatory cytokines.10 Depending on
the activation stimuli, M2-macrophages can be subdivided in
3 partially distinct phenotypes: M2a (resulting from IL-4/13
stimulation), M2b (induced by immune complexes stimulation
in the presence of toll-like receptor ligands), and M2c (on
exposure of macrophages to anti-inflammatory stimuli, such
as glucocorticoid hormones, IL-10, or transforming growth
factor-β).11
Thus, macrophage polarization is an important component
of both the innate and adaptive immune responses to pathogens and tumor cells, balancing the proinflammatory and antiinflammatory states to fine-tune the most appropriate type and
intensity of immune response to a microbial or neoplastic threat.
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Of Mice and Men…in
Macrophage Polarization
Mice and humans share ≈80% of orthologous genes, whereas
the frequency of mouse genes without any human homolog
is <1%.12 Nonetheless, significant differences between mice
and humans exist in the development of the immune system
as well as in the activation of both the innate and adaptive
immune responses. Concerning macrophage polarization,
both similarities and differences have been reported between
man and mouse, as summarized in the Table.
In particular, one of the best surface markers used for determining the distribution and function of mouse macrophages is
Ly-71 (F4/80),13,30 which is believed to play an immunoregulatory role through the interaction with an unidentified cellular
ligand expressed by other immune effectors cells.31,32 F4/80
expression by tumor-associated macrophages (TAM) has been
documented in many types of tumors, either naturally occurring or experimentally induced. To date, no human homolog
of F4/80 has been reported, but the closely related molecule
epidermal growth factor-like module-containing mucin-like
hormone receptor-like 2 provides a sensitive marker for identification of TAM as well as of macrophages in healthy human
tissue. CD97 is, conversely, a human macrophage marker
also expressed in the mouse and highly similar to epidermal
growth factor-like module-containing mucin-like hormone
receptor-like 2. Of note, all these antigens belong to the family of G-protein–coupled receptors (R).33,34
M1- and M2-Phenotypic Markers
Surprisingly, there are only a few cell surface markers that
have been clearly associated with mouse M1-polarization
(Table). In contrast, selective and restricted expression of
markers typical of alternative macrophage polarization has
been described in both human and mouse studies. Murinerestricted macrophage markers of M2-polarization lacking
homologs in human include the chitinase-like proteins YM1
and YM2,35,36 members of the glycosyl-hydrolase family 18,
for which it has been hypothesized a function either as lectinbinding proteins or cytokines.20 Another murine-restricted
macrophage marker of M2-polarization is FIZZ1 (found in
inflammatory zone 1),36 for which no human homolog has
been described.
The M2- and Th2-polarizing cytokine IL-4 upregulates the
expression of chemokine ligands (CCLs), such as CCL13,
CCL14, CCL17, CCL18, CCL22, and CCL24, from human
macrophages. Three of these upregulated chemokines lack
murine orthologs, such as CCL14 (only human), CCL18 (for
which a pseudogene has been described in the mouse), and
CCL23 (showing a low degree of homology with murine
CCL6), whereas CCL17 and CCL24, which do have murine
orthologs, are exclusively upregulated in humans.20
Finally, some confusion has also been generated by inappropriate use of nomenclature. CCL2 has been described as
marker of M2-polarization in murine macrophages, whereas
CCL13 is a marker of human M2-phenotype in humans. The
situation is complicated by the fact that, in humans, CCL2 is
different from CCL13 (homolog of murine CCL2), and it is a
marker of M1-polarization.
Macrophage Polarization and Viral Infections
Pathogens have evolved ingenious strategies to circumvent
host immune responses as part of the constant evolutionary process occurring in all living organisms. In this scenario, macrophages are endowed with strategies to neutralize
pathogenic challenges, while preserving host integrity. In
steady-state conditions, macrophages perform multiple housekeeping functions governed by their differentiation state, tissue distribution, and signals from the microenvironment. As
discussed below, an excessive polarization may be associated
with comorbidities and be detrimental to the host.
Viral pathogens causing chronic diseases, such as human
cytomegalovirus (HCMV), human herpes virus 8, and the
HIV-1, have evolved strategies to take advantages from macrophage polarization to favor their own survival in the host in
a latent state.
Macrophage Polarization and HCMV Infection
HCMV, also known as human herpes virus 5, is a member
of the family of Herpesviridae (Betaherpesvirinae ­subfamily)
and infects 60% to 90% of the adult population, leading to
a life-long infection of the host (“herpes is forever…”).37
Infection by HCMV leads to morbidity and mortality in
immunocompromized individuals, such as AIDS patients,
organ transplant recipients, congenitally infected neonates,
and cancer patients undergoing chemotherapy.38
After the initial primary infection of host epithelial cells by
contact with HCMV-contaminated body fluids, HCMV replicates and spreads via peripheral blood to disseminate in multiple organs.39 HCMV infection causes a wide range of overt
organ diseases, including retinitis, gastro-intestinal symptoms,
hepatitis, and interstitial pneumonia attributable to the broad
in vivo cellular tropism of the virus.39 Human monocytes are
responsible for the systemic spreading of HCMV,38–40 representing primary target in vivo and sites of viral latency and
persistence; moreover, tissue macrophages are the most prominent infiltrating cell type found in HCMV-infected organs.41,42
Their aberrant function after HCMV infection has been also
implicated in the pathogenesis of atherosclerosis.43,44
Alfano et al Macrophage Polarization, HIV and Cancer 1147
HCMV-activated monocytes exhibit increased secretion
of cytokines and chemokines, adhesion to endothelial cells
and transendothelial migration, suggesting their predominant
M1-polarization,45–47 as confirmed by transcriptional profiling
studies of HCMV-infected macrophages.48 The secretion of
M1-associated cytokines and chemokines, such as IL-1β,
IL-6, and tumor necrosis factor-α, in addition to further
shaping macrophages toward an M1-phenotype, enhances
virus replication and dissemination.45,46
Macrophage Polarization and Human Herpes
Virus 8 Infection in HIV-1+ Individuals
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Kaposi (angio)sarcoma (KS) is one of the most common
tumors in therapy-naïve HIV-1+ males, in whom it may
acquire features of tissue damage and spreading not observed
in its endemic variant.49,50 The pathogenesis of both endemic
and HIV–associated KS has been unequivocally linked to the
infection by human herpes virus 8, also termed Kaposi sarcoma–associated herpes virus.24 The role of macrophages in
the pathogenesis of AIDS–related KS has been well described,
because CD169+ macrophages were found associated to the
typical KS lesions.49
The establishment of M1-/T helper cells 1-biased immune
responses involving CD8+ T cell activation and leading to the
production of T helper cells 1 cytokines that promote the progression of KS is supported by studies showing that administration of IFN-γ or tumor necrosis factor-α to patients with
HIV-1+ leads to KS development and disease progression.50,51
Because IFN-γ and other proinflammatory cytokines are produced during HIV-1 infection, together with the progressive
state of immunodeficiency, they may contribute to determine the faster progression of KS compared with the disease
observed in HIV-negative individuals.51
Macrophage Polarization and HIV-1 Infection
HIV-1 is a pathogenic human retrovirus of the lentivirinae
subfamily that profoundly dysregulates the human immune
system by causing a state of chronic immune activation ultimately leading to a progressive severe immunologic deficiency with depletion of CD4+ helper T cells known as AIDS.
During HIV-1 infection, monocytes and macrophages play a
fundamental role as viral reservoirs throughout all the stages
of disease, promoting both immune dysregulation and virus
dissemination and representing, together with CD4+ T cells,
one of the major barriers to HIV-1 eradication in the setting of
highly controlled virus replication by means of combination
antiretroviral therapy.52 In particular, tissue macrophages contribute to the establishment of viral reservoirs as consequence
of their ubiquitous distribution, long half-life, relative insensitivity to the cytopathic effects of virus replication (unlike CD4+
T cells) and, finally, to their peculiar capacity of producing and
storing mature HIV virions in intracellular compartments of
debated origin.53 Indeed, HIV-infected macrophages in tissues
are credited to represent a crucial cell population, contributing
to the viral spreading particularly during the AIDS phase characterized by a severe CD4+ T cell depletion.54–56
A standing issue is whether different, precommitted monocytes exist.57 In particular, CD16+ monocytes are expanded in
blood and tissues during pathological conditions characterized
by chronic inflammation, including inflammatory bowel disease, cancer, and AIDS.57 Indeed, CD14+CD16+ monocytes are
the predominant subset of monocytes, in which HIV infection
is hosted,58 and represent a main vehicle by which the virus
passed across the blood–brain barrier to colonize the central
nervous system.59
Several authors have investigated the role of cytokines, chemokines, and bacterial products on either the susceptibility
of human monocyte–derived macrophages (MDM) to HIV-1
infection or on the functional polarization of these cells. In
vitro, HIV-1 infection has been reported to drive human MDM
toward an M1-like phenotype,60,61 although unlike that observed
after stimulation with lipopolysaccharide, HIV-1–driven polarization does not involve a toll-like receptor–­dependent pathway
and does not result in the production of proinflammatory cytokines, such as IL-1-β or IL-6 (Figure).60 However, HIV-primed
MDM are hyperresponsive to different stimuli, including lipopolysaccharide, CL097 (toll-like receptor 7/8 agonist), and
polyinosinic:polycytidylic acid.60 Moreover, HIV-1 infection of
human MDM causes an increased secretion of M1-associated
chemokines, including CCL3, CCL4, and CCL5 (ligands of
the CC-chemokine receptor 5 [CCR5], the main HIV-1 entry
coreceptor), and downregulation of M2-associated markers,
such as CD163, the mannose receptor CD206, CCL18, and
IL-10.60,61 These findings support the hypothesis that HIV-1
infection of macrophages induces or primes their polarization
toward a proinflammatory, M1-phenotype likely contributing,
among other effects, to the establishment and maintenance of
state of chronic activation that is nowadays credited to represent a major determinant of HIV-1 disease progression.62–64
Experimental polarization of human macrophages has been
obtained by our group by exposing 5- to 7-day-old MDM to
either IFN-γ plus tumor necrosis factor-α (M1) or IL-4 (M2a)
for 18 h before HIV-1 infection after removal of the cytokines.14
In these experimental conditions, both M1- and M2a-MDM
have shown a decreased capacity to support productive CCR5dependent (R5) HIV-1 replication in comparison with unpolarized MDM (whereas CXC chemokine receptor 4-dependent
infection was never observed to be productive in either polarized or unpolarized cells),14 however with important differences between M1 and M2a cells. In fact, a potent restriction
of HIV-1 replication occurring at a preintegration level of the
viral life cycle was shown in the case of M1−, but not of M2aMDM, and was associated with a downregulation of primary
CD4 receptor and with the secretion of CCR5-binding chemokines (CCL3, CCL4, and CCL5) ultimately resulting in
decreased levels of HIV-1 DNA synthesis.14
Independently, some microRNA (miR) credited with anti–
HIV-1 effects, including miR-28, miR-150, miR-223, and
miR-382, have been described as upregulated in MDM stimulated with type-I IFN.40 In this regard, a contribution of miR155 to poly (I:C)-induced anti-HIV-1 effects observed during
primary macrophage infection has been recently reported.62–64
In addition, IFN-γ stimulation of human MDM has been
shown to increase several natural restriction factors for HIV-1
infection, including tripartite motif5α, cyclophilin A, apolipoprotein B mRNA editing enzyme, catalytic polypeptidelike3G, 3 prime repair exonuclease 1, tripartite motif 22, and
Bst-2/theterin.40
1148 Arterioscler Thromb Vasc Biol June 2013
M1-MDM
R5 HIV-1 replication
HIV-1 attachment and
entry receptors
Cytokine and chemokine
secretion
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HIV-1 life cycle
interference
HIV-1 restriction factor
expression
IFN- γ
+
TNF- α
IL-4,
IL-13
Unpolarized MDM
M2a-MDM
+/-
++++
++
DC-SIGN (-)
CD4 (+/-)
CCR5 (++)
DC-SIGN (+)
CD4 (+++)
CCR5 (++)
DC-SIGN (+++)
CD4 (+)
CCR5 (++)
IL-6, IL-12, TNF-α, CCL2,
CCL3, CCL4, CCL5
CXCL8, CXCL9, CXCL10,
CXCL11
low to undetectable
IL-1ra, IL-10, CCL13, CCL14,
CCL20, CCL22, CCL23
Entry, pre-integration
(post-integration)
n.a.
Post-integration
APOBEC3A
(APOBEC3G, SAMHD1,
TRIM22)
APOBEC3G, TRIM22
Undefined
Figure. Human monocyte–derived macrophage (MDM) polarization and HIV-1 infection in vitro. The figure summarizes published and
unpublished results from our as well as other laboratories.14,15,21,96 DC-SIGN indicates dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin; IFN, interferon; IL, interleukin; n.a., not applicable; TNF, tumor necrosis factor; and TRIM, tripartite motif.
In our experience, M2a-polarization of human MDM
is characterized by less potent, but more durable inhibition
of HIV-1 replication, with no detectable impairment of
HIV-1 DNA synthesis,14 therefore implying the induction
of an interference mechanism acting at a postintegration
level.14,15,40 Recently, we have reported that expression of
dendritic cell–specific intercellular adhesion molecule-3grabbing nonintegrin is present and enhanced in unpolarized
and M2a-MDM, respectively, whereas it downregulates
M1-cells,21 therefore representing a potentially useful marker
to distinguish between M1- and M2-macrophages in vivo.
Dendritic cell–specific intercellular adhesion molecule3–grabbing nonintegrin expression by M2a-MDM, on the
one hand, may compensate for the decreased levels of CD4
on the surface of these cells, but, on the other hand, facilitate
virion transmission to CD4+ T cells, in analogy to its already
demonstrated role in dendritic cell.65 Therefore, M2apolarization likely induces both restrictive and permissive
factors of HIV spreading, unlike M1-cell polarization. In this
regard, a distinctive feature between M1- and M2-MDM is
their ability to internalize HIV-1 virions, in that it has been
reported to be significantly increased in M1-MDM versus M2or unpolarized MDM.66 Such a different endocytic capacity
may ultimately affect the different susceptibility of MDM to
HIV-1 infection in addition to impact on both their antigenpresenting function and their ability to transfer virions to other
target cells.66
Based on the differential profiles of monocyte activation
observed in patients at different stages of disease, in 2010
Herbein and Varin have proposed a model, whereby the macrophage activation or polarization state changes during the
course of disease, with an M1-phenotype dominating during
the early phase of the disease and an M2a-profile emerging
during the chronic phase of disease, leading to macrophage
deactivation (M2c) in its later stage.67
The introduction of combination antiretroviral therapy
has significantly ameliorated the quality of life of infected
individuals and prolonged their life expectancy. Such an
increased life-span has been, however, associated with a
significant change in HIV-1 infection comorbidities, including an increased incidence of solid cancers (discussed later)
and of cardiovascular complications, including accelerated atherosclerosis and pulmonary hypertension.68,69 In this
regard, the importance of macrophage polarization in the
pathogenesis of atherosclerosis, and in particular the switch
between the initial phase of atherosclerotic plaque formation,
characterized by M2 predominance overturned by murine
M1-macrophages with ensuing plaque growth has been discussed elsewhere.70,71 However, such a switch has not been
observed in humans, in whom the presence of both M1- and
M2-macrophages during human atherosclerotic plaque development has been reported.70,71
Polarized Macrophages and Tumor
Pathogenesis
TAM have been clearly involved in many events in tumor
pathogenesis, although their role is still debated as a function
of their intra- versus peritumoral localization and of the
reciprocal interaction with malignant and stromal cells in the
local microenvironment.72,73 Peritumoral TAM displaying a
proinflammatory M1-like phenotype (ie, expressing cytokines,
such as IFN-γ, IL-1β, and IL-6, and favoring antitumor immune
Alfano et al Macrophage Polarization, HIV and Cancer 1149
Table. Expression of Cell Surface and Soluble Antigens Associated With Murine and Human Functional Macrophage (Mø)
Polarization
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Mø
Mouse
Human
M1
Cell surface: CD16 (FcγRIII), CD86, MHC-II antigens
Soluble: CXCL9, CXCL10, CXCL11, TNF-α
Other: iNOS
Cell surface: CD4 (downregulation), CCR7, IL-2Rα, IL-15Rα, CD80, CD86,
MHX-II antigens, TLR2, TLR4
Soluble: CCL2, CCL3, CCL4, CCL5, CCL20, CXCL8, CXCL9, CXCL16, IL-1β,
IL-7, IL-12, IL-18, IL-23, TNF-α, ROI
Other: iNOS
References
M2
Cell surface: scavenger R, MRC1
Soluble: CCL2, CCL22, IL-10, YM1, YM2, FIZZ1
Other: Arginase1, HO-1
Cell surface: CD36, CD163, CXCR1, CXCR2, Dectin-1, DCL-1, SR-A, DCIR/ 9,15,16,20–23
LLIR, Scavenger R, MRC1, BIGH-H3, β2 integrins, DC-SIGN
Soluble:
CCL1, CCL13, CCL14, CCL17, CCL18, CCL20, CCL22, CCL23, CCL24, IL1ra, IL-10, IGF
Other: Fibronectin, SPHK1, HO-1
TAM
Cell surface: CD11b, CD14, CD36, CD45, CD68, CD97,
CD163, CD200/ CD200R, CD204, CD206, CCR1, CCR2,
CXCR1, IL-4/IL-13R, CSF1R, MHC-II antigens, VEGFR1,
CR3, FcR, SR-A, MARCO, Mannose R, Dectin-1, Dectin-2,
TLRs, F4/80 (Ly-71) antigen
Soluble: CCL2, CCL5, CCL13, CCL22, CXCL9, CXCL10,
CXCL16, IL-10
Other: HO-1
Cell surface: CD4 (downregulation), CD11b, CD14, CD23, CD36, CD45,
CD68, CD97, CD163, CD200/CD200R, CD204, CD206, CCR1, CCR2,
CXCR1, CXCR4, IL-4/13R, CSF1R, MHC-II antigens, VEGFR1, CR3, FcR,
SR-A, MARCO, Mannose R, Dectin-1, Dectin-2, TLRs, MMP2, MMP9,
B7H4, FRb, EMR2
Soluble: IL-6, IL-10, IL-12, TNF-α, CCL2, CCL5, CCL13, CCL18, CCL22,
CXCL9, CXCL10, CXCL16
Other: STAT-3
9,13–19
3,22,24–29
Upregulated expression of M1 or M2 markers vs unpolarized cells was mainly obtained from in vitro studies. Markers of TAM were defined from ex vivo studies and
compared in terms of expression with the levels observed in macrophages isolated from tumor-free tissue. In bold are indicated markers shared by murine and human
MDM.
CR3 indicates complement R3; CSF1R, colony stimulating factor 1 R; DCIR/LLIR, lectin-like immunoreceptor; DCL1, DEC-205-associated C-type lectin-1; EMR2,
epidermal growth factor-like module-containing mucin-like hormone receptor-like 2; FRb, folate R b; HO-1, heme oxygenase-1; IGF, insulin growth factor; IL-1ra, IL-1
receptor antagonist; MDM, monocyte-derived macrophage; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; MRC1, mannose R mannose R, C
type 1; ROI, reactive oxygen intermediates; SPHK1, sphingosine kinase 1; SR-A, scavenger R class A; STAT-3, signal transducer and activator of transcription 3; TLR,
toll-like receptor; and VEGFR1, vascular endothelial growth factor R1.
response by T helper 1 cells)74 have been associated with
prevention of tumor development and a good prognosis.75–78
The complexity of the role of M1-polarized macrophages in
the context of cancer development is illustrated by the observation that, on the one hand, M1-polarized TAM promote
expression of galectin-3 by colon tumor cell that further induce
more macrophage infiltration leading to an amplification of
immune responses against tumor cells,74 but, on the other
hand, they contribute to the maintenance of chronic inflammation that leads to accumulation of DNA mutations favoring
early steps of tumorigenesis. Conversely, intratumoral TAM
cell count has been correlated with depth of invasion, lymph
node metastasis, and staging of colorectal carcinoma, suggesting that intratumoral macrophages may promote a more
aggressive behavior of cancer cells.79,80
Overall, most studies on different malignant cancers,
including lymphomas, intestinal type gastric cancers, pancreatic cancers, nongynecologic leiomyosarcomas, and thyroid
cancers, indicate that the presence of anti-inflammatory TAM
in the tumor microenvironment is associated with a worse
prognosis. In this regard, TAM are believed to orchestrate
various aspects of cancer biology, such as tumor progression,
angiogenesis, tumor growth, and actual metastasis in a context of immunosuppression.72,81,82 In particular, TAM represent variants of a general M2-polarization phenotype based
on the expression of a series of markers, such as CD163, the
R for Fc fragment of IgG, C-type lectin domain proteins,
and heat shock proteins characteristically expressed by alternatively activated macrophages.83–85 In addition, the tumor
microenvironment is characterized by the presence of several
anti-inflammatory cytokines, such as IL-4, IL-10, IL-13, and
transforming growth factor-β, that lead resident or recently
migrated macrophages to adopt an M2-phenotype.86
In addition to growth factors, cytokines, and chemokines,
TAM (M2) express molecules, which affect tumor cell
proliferation, angiogenesis, and dissolution of connective
tissues, such as matrix metallo-proteinases, thus contributing
to matrix degradation needed for promoting angiogenesis
and release of growth factors,87 plasmin, and urokinasetype plasminogen activator and its receptors urokinase-type
plasminogen activator receptor.7,87
Translational Medicine: A Role for
Macrophage Polarization in Cancer Therapy?
This review focuses on the important roles of macrophages in
viral infection and cancer, which qualifies them as potential
druggable targets, aiming at decreasing macrophage accumulation, inducing their depletion, suppressing TAM-induced
tumor angiogenesis, reprogramming macrophage polarization, and using these cells as functional vehicles. TAM are
today considered putative targets for therapeutic intervention.81 In this regard, destruction of tissue macrophages
with clodronate-loaded liposomes has also been shown to
inhibit several tumorigenic steps, although this strategy has
been investigated only in animal models, whereas the use of
bisphosphonates in humans has been associated with severe
adverse events.88 Furthermore, persistent depletion of macrophages could also potentially expose individuals to acquire
1150 Arterioscler Thromb Vasc Biol June 2013
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more easily mycobacterioses and other infectious diseases.88
As alternative approach, promotion of a switch of TAM polarization from M2 to M1 has also been investigated as strategy
to reduce tumor growth and invasion.9
IFN-γ administration was observed to activate a tumoricidal activity of TAM in a large clinical study in patients with
ovarian cancer by inducing a phenotypic switch.89 A recent
study performed in a pancreatic ductal adenocarcinoma model
has reported that anti-CD40 Abs promoted an antitumor effect
and induced high expression of M1-associated markers (such
as major histocompatibility complex class II antigens and
CD86) in macrophages.90 Zolendronic acid has been shown to
inhibit macrophage migration, proliferation, and secretion of
tumor-promoting factors, such as matrix metallo-proteinases
9. Furthermore, both zoledronic acid, C phosphate G, antiIL10 and anti-IL10 receptor reversed the M2-polarization bias
of TAM; in the case of Zolendronic acid, this was associated
with an increased expression of inducible NO and with the
downregulating of IL-10 and vascular endothelial growth factor secretion.91,92 In addition, the plasma protein histidine-rich
glycoprotein, endowed with antiangiogenesis effect, induced
TAM polarization toward an M1-like phenotype by inducing
the downregulation of the placental growth factor, a member
of the vascular endothelial growth factor family.93 In mice,
histidine-rich glycoprotein promoted antitumor immune
response and normalization of the vessel network.93 Other
therapeutic strategies focused to affect macrophages polarization include trabectedin94 and statins.95
Conclusions
The MP system is central to both the innate and adaptive
immune responses to microbial invaders and cancer cells.
Its well known plasticity can be transiently overcome by the
possibility of polarizing its activation profile according to a
range of variable functional aspects at the extreme poles, of
which there are M1 and M2 opposite programs of macrophage activation. In the case of HIV-1 infection, although
M1-polarization does not prevent the in vitro infection of
these cells, it creates a hostile environment for retrovirus
replication affecting multiple steps of its life cycle, both at
pre- and (likely) postintegration levels, while, at the same
time, the increased expression of major histocompatibility complex class II antigens and of secreted factors could
potentially favor the clearance of infected cells by the adaptive arm of the immune system. Similar considerations could
be made for the role of MP polarization in cancer cell biology and progression, converging to a general picture, in
which MP tend to occupy a more prominent role than earlier
suspected in the pathogenesis of these prominent diseases
affecting mankind.
Acknowledgments
We thank Edana Cassol and Luca Cassetta, who have established the
M1/M2-polarization model of HIV infection in our laboratory and
Antonio Sica (Humanitas Clinical and Research Center, Milano)
for his helpful suggestions. F. Graziano and L. Genovese performed
this study as partial fulfillment of their PhD of the International PhD
School in Molecular Medicine, Università Vita-Salute San Raffaele,
Milano, Italy.
Sources of Funding
This article was supported in part by the grants to M. Alfano and
G. Poli from the Italian Ministry of Health Grant Program of AIDS
Research 2009 to 2010.
Disclosures
None.
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Macrophage Polarization at the Crossroad Between HIV-1 Infection and Cancer
Development
Massimo Alfano, Francesca Graziano, Luca Genovese and Guido Poli
Arterioscler Thromb Vasc Biol. 2013;33:1145-1152
doi: 10.1161/ATVBAHA.112.300171
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