When two is better than one: macrophages
and neutrophils work in concert in innate
immunity as complementary and
cooperative partners of a myeloid
Manuel T. Silva1
Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, Porto, Portugal
RECEIVED AUGUST 12, 2009; REVISED SEPTEMBER 6, 2009; ACCEPTED SEPTEMBER 21, 2009. DOI: 10.1189/jlb.0809549
The antimicrobial effector activity of phagocytes is cru-
cial in the host innate defense against infection, and the
classic view is that the phagocytes operating against
intracellular and extracellular microbial pathogens are,
respectively, macrophages and neutrophils. As a result
of the common origin of the two phagocytes, they
share several functionalities, including avid phagocyto-
sis, similar kinetic behavior under inflammatory/infec-
tious conditions, and antimicrobial and immunomodula-
tory activities. However, consequent to specialization
during their differentiation, macrophages and neutro-
phils acquire distinctive, complementary features that
originate different levels of antimicrobial capacities and
cytotoxicity and different tissue localization and lifes-
pan. This review highlights data suggesting the perspec-
tive that the combination of overlapping and complemen-
tary characteristics of the two professional phagocytes
promotes their cooperative participation as effectors and
modulators in innate immunity against infection and as
orchestrators of adaptive immunity. In the concerted ac-
tivities operating in antimicrobial innate immunity, macro-
phages and neutrophils are not able to replace each
other. The common and complementary developmental,
kinetic, and functional properties of neutrophils and mac-
rophages make them the effector arms of a myeloid
phagocyte system that groups neutrophils with members
of the old mononuclear phagocyte system. The use by
mammals of a system with two dedicated phagocytic
cells working cooperatively represents an advantageous
innate immune attack strategy that allows the efficient
and safe use of powerful but dangerous microbicidal mol-
ecules. This crucial strategy is a target of key virulence
mechanisms of successful pathogens. J. Leukoc. Biol.
87: 000–000; 2010.
The outcome of the presence of a microbe within a host is
dependent on the nature of the host-microbe interaction .
When such an interaction progresses with advantage to the
microbe, as the pathogenicity factors of the microbe overcome
the immune defenses of the host, an infectious disease ensues.
On the contrary, when the host is capable of mounting an im-
mune response that provides a balanced protection, infection
is prevented or controlled.
When infectious agents pass the defenses of epithelia and
invade normally sterile body territories, they encounter innate
antimicrobial mechanisms. When protective, these mechanisms
involve the efficient intervention of several immune and non-
immune cells but are crucially centered on the activities of the
dedicated phagocytes, monocytes/macrophages, and neutro-
phils. This concept is in line with the seminal studies by
Metchnikoff , who created the theory of phagocytosis and
highlighted the phagocytic and antimicrobial abilities of mac-
rophages and microphages (neutrophils).
However, in the following years, neutrophils were largely
underestimated, and macrophages acquired the status of the
essential phagocytes. This view was reflected in the exclusion
of the neutrophil in the initial attribution in 1967 of the label
“professional phagocytes” to macrophages  and in the cre-
ation in 1969 of the mononuclear phagocyte system that
grouped macrophages and their precursors (monocytes and
bone marrow precursors) .
About 20 years later, neutrophils started to emerge as arche-
typical immune cells with rich effector and immunomodula-
tory functions , which led to the addition of neutrophils to
monocytes/macrophages in the updated version of the con-
cept of professional phagocytes .
Besides being precursors of macrophages [7–9], monocytes
have progressively being recognized as relevant, direct effec-
tors of antibacterial innate immunity [10, 11].
1. Correspondence: Instituto de Biologia Molecular e Celular, Rua do
Campo Alegre 823, 4150-180 Porto, Portugal. E-mail: firstname.lastname@example.org
Abbreviations: DC?dendritic cell, HNP-1?human neutrophil peptide 1,
MPO?myeloperoxidase, PRR?pattern recognition receptor,
PS?phosphatidylserine, RNS?reactive nitrogen species, ROS?reactive
0741-5400/10/0087-0001 © Society for Leukocyte Biology
Volume 87, January 2010
Journal of Leukocyte Biology 1
Epub ahead of print October 30, 2009 - doi:10.1189/jlb.0809549
Copyright 2009 by The Society for Leukocyte Biology.
DCs  were added later to the mononuclear phagocyte
system . They are a group of primarily APCs and immuno-
modulatory macrophagic cells that display heterogeneous
phagocytic activity . However, DCs have a limited capacity
for lysosomal degradation of phagocytosed material , and
in contrast to neutrophils and macrophages, they are not in-
volved in direct pathogen clearance .
This review is centered on the participation of phagocytes in
the antimicrobial mechanisms of innate immunity in mam-
mals. Detailed reviews are available about neutrophils [17–19]
and monocytes/macrophages [10, 20, 21].
SPECIALIZED FEATURES COMPLEMENT
THE COMMONALITIES OF
MACROPHAGES AND NEUTROPHILS
The initial view that neutrophils and macrophages arise from a
common late bone marrow precursor [22, 23] has been con-
firmed by results showing that these phagocytes originate from
stem cells that differentiate through common myeloid progen-
itors and granulocyte/macrophage progenitors [24–26]. This
common origin explains that the same functional defects can
affect neutrophils and macrophages simultaneously  and
that neutropenia and monocytopenia can occur concomitantly
in several hematological disorders . Their common origin
also explains that these two professional phagocytes share sev-
eral characteristics: (i) Like macrophages, neutrophils are av-
idly phagocytic, and both phagocytes use a large array of anti-
microbial mechanisms that involve oxidants, granule proteins,
and iron-withholding molecules (reviewed in refs. [18, 29,
30]). ROS are produced by a NADPH oxidase complex.
Phagocytes can also produce RNS, and induced NO synthase is
involved in the production of the microbicidal NO. The ROS
member superoxide combines with the RNS NO to form a
product—peroxynitrite—which is more bactericidal and cyto-
toxic than either of its precursors . (ii) Macrophages and
neutrophils have similar transcriptional profiles and coexpres-
sion of several genes [25, 32, 33] with common secretion of
some cytokines and chemokines [34–36]; this explains why
monocytes/macrophages and neutrophils recruit inflammatory
phagocytes (see below). (iii) Macrophages and neutrophils
have overlapping expression of cell surface receptors for Igs
and complement  and for several chemokines [34, 35],
which explains that under infectious/inflammatory situations,
neutrophils and monocytes are concomitantly recruited (see
below). (iv) The two phagocytes have overlapping expression
of some antigens [8, 38], which explains the difficulty in selec-
tively depleting neutrophils or monocytes/macrophages with
antibodies (see below). (v) Monocytes/macrophages and neu-
trophils express PRRs ; additionally, neutrophils shuttle to
lymph node microorganisms and bacterial antigens [40–42],
regulate macrophage/DC functions , deliver bacterial anti-
gens to these cells, helping in the cross-presentation of bacte-
rial antigens to T cells [44, 45], and present antigens to T cells
directly , indicating that neutrophils cooperate with mac-
rophages in the orchestration of adaptive immune responses
[17, 47, 48]. (vi) Macrophages are the main scavenger phago-
cyte, efficiently removing erythrocytes, apoptosing, and dead
cells and cell debris , but when the scavenging capacity of
macrophages is overwhelmed, neutrophils may function as a
backup system . (vii) Conversion of neutrophils into mac-
rophages or DCs has been reported. Postmitotic human neu-
trophils cultivated under defined conditions generated cells
with morphologic, cytochemical, and phenotypic features of
macrophages . Neutrophils cultured in the presence of
M-CSF differentiate into F4/80-positive macrophages . Im-
mediate precursors of end-stage  or mature  neutro-
phils can acquire characteristics of DCs under defined cultural
conditions. (viii) Finally, mobilization of neutrophils and
monocytes to infectious/inflammatory sites follows similar ki-
netics (see below).
Additionally, the progressive modifications characteristic of
macrophage and neutrophil maturation  lead to the spe-
cialization of each phagocyte, providing them with distinct in-
dividual properties that complement the similarities associated
with their common origin.
Although varying among mammals, the antimicrobial capacity
of neutrophils is higher compared with that of macrophages [2,
53–55]. The former are equipped with a huge assortment of mi-
crobicidal mechanisms and use multiple antimicrobial molecules
stored in enormous amounts in granules sequentially formed
during granulopoiesis [54, 56]. Production of ROS is most promi-
nent in neutrophils as compared with macrophages . Follow-
ing phagocytosis, neutrophils use the “cross-talk” between oxi-
dants and granule proteins to attack ingested microbes in a col-
laborative way . Several antimicrobial proteins that are an
important part of the neutrophil arsenal are lacking or scarce in
the tissue macrophage [57–60]. This is the case of defensins and
cathelicidins, the major families of mammalian antimicrobial pep-
tides of neutrophils , and lactoferrin. The bactericidal/per-
meability-increasing protein is also a specific component of neu-
trophils . MPO is an important enzyme involved in oxidative
antimicrobial mechanisms of neutrophils oxidizing chloride ions
to the strong hypochlorous acid, which is the most bactericidal
oxidant known to be produced by phagocytes . MPO is
present in circulating mammal monocytes but is lost as these ma-
ture into macrophages , which correlates with decay in anti-
microbial activity .
The pattern of distribution of neutrophils and macrophages
correlates with their different antimicrobial capacities (and
associated cytotoxicity) and different lifespans. The abundant
and powerful antimicrobial neutrophil granule molecules and
oxidants are not selective against microorganisms but rather,
unspecific biocidal molecules with high cytotoxicity and poten-
tial tissue-damaging activity [19, 65]. This makes the activated
neutrophil a dangerous cell that must be tightly controlled.
Neutrophils are thus rare in the tissues and body cavities; they
are present as quiescent cells in blood and bone marrow as
reserve pools, ready to be activated and put to work only
where, when, and while required . This “surgical” actua-
tion is possible, as neutrophils are present in large numbers in
the reserve pools, are recruited quickly, and are short-lived
. In contrast, the lesser microbicidal and thus, less cyto-
toxic resident macrophage is long-lived  and has species-
variable , self-renewal capacity . Therefore, it is a cell
well suited to reside in all body compartments  as the first
Journal of Leukocyte Biology
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myelopoiesis ? phagocytosis ? chemotaxis ? antimicrobial mecha-
nisms ? pathogenicity mechanisms
Journal of Leukocyte Biology
Volume 87, January 2010