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
Volume 87, January 2010
phagocyte that invading pathogens encounter, irrespective of
their route of entry . Strategically positioned, tissue resi-
dent macrophages thus function as sentinels that recognize,
phagocytose, and signal invading pathogens rapidly.
These distinctive features explain that macrophages and
neutrophils are not able to replace each other as crucial ele-
ments of antimicrobial innate immunity, as indicated by the
pathology associated with some human and murine phagocyte
deficiencies . The conjugation of overlapping and comple-
mentary characteristics of the two professional phagocytes al-
lows for a cooperative participation as effectors and modula-
tors in innate immunity, as will be reviewed later.
NEUTROPHILS AND MONOCYTES
CLUSTER WITH MACROPHAGES AND
DCS AT INFECTIOUS FOCI
The number of resident phagocytes in resting tissues is small,
but following microbial invasion, neutrophils [19, 66] and
monocytes [7, 8] are recruited quickly to infectious foci. Usu-
ally neutrophils are the first phagocytes to arrive at those foci
. Neutrophils change their phenotype under infectious/
inflammatory situations (Table 1), becoming activated by mi-
crobial products  and by attracting molecules [19, 67].
This activation leads to the expression of powerful antimicro-
bial activities  and to the controlled release of granule
components  and is crucial for the effective innate immu-
nity. Recruited monocytes give rise locally to inflammatory
macrophages [7, 8] and to a subset of DCs , both partici-
pating in innate antimicrobial defenses.
This pattern of mobilization of the two professional phago-
cytes occurs early in the inflammatory response induced by
infection with extracellular  or intracellular  patho-
gens. Mobilization of inflammatory neutrophils and monocytes
is coordinated by complex networks of cytokines and chemo-
kines that are produced in the context of the inflammatory
process triggered by infection [81, 82] (Table 2). This inflam-
matory response and the associated cytokine and chemokine
release are induced by microbial molecules that interact with
complement  and with local cells. These include site-spe-
cific resident cells, mainly resident macrophages [83, 84, 98,
99], and DCs [100, 101]. To detect the occurrence of infec-
tion with the consequent recruitment of inflammatory neutro-
phils and monocytes, resident macrophages and DCs use in-
variant PRRs  that recognize conserved pathogen-associ-
ated molecular patterns present on extracellular and
intracellular pathogens . As PRRs are also expressed by
neutrophils , these participate in the triggering of innate
immune responses [17, 47]. Upon detecting the presence of
invading pathogens, tissue macrophages (Fig. 1, upper panel,
A) and DCs secrete CXCL8 (IL-8), CXCL1/2/3 (growth-re-
lated oncogene; MIP-2 in the mouse), CCL2 (MCP-1; JE in the
mouse), and CCL3/4 (MIP-1) [10, 83, 98], which attract neu-
trophils and monocytes that become activated [19, 67].
Recruited, activated neutrophils exhibit relevant immuno-
modulatory abilities, which result in the release of proinflam-
matory cytokines and chemokines, an important activity that
amplifies the initial chemotactic role of resident macrophages
and DCs. Among the cytokines secreted by activated neutro-
phils are the proinflammatory IL-1? and TNF-? [5, 36], which
stimulate the production by several cells of chemokines that
primarily attract neutrophils  or monocytes . The
cytokine IL-17 is typically described as relevant in chronic in-
flammation and autoimmune diseases , but it is also an
efficient first line of defense during the innate immune re-
sponse associated to infection [106–109]. IL-17 acts on neutro-
phils by indirect expansion of their numbers through regula-
tion of G-CSF and by recruitment through regulation of che-
mokine expression by several cell types . Among these
chemokines are the important neutrophil-attracting CXCL1,
CXCL2, and CXCL8. IL-17 is produced mainly by ?? T cells,
CD4? TH17 lymphocytes, and NKT cells [109–111], but it is
also produced by neutrophils [112, 113]. Thus, neutrophils
are here using another way to increase and sustain their pres-
ence at infectious/inflammatory sites, as they do with the di-
rect secretion of neutrophil-attracting chemokines. This is im-
portant, as inflammatory neutrophils, having a short lifespan
, have to be recruited continuously as long as they are
needed. As in the case of several proinflammatory chemo-
kines, in infectious/inflammatory situations during innate im-
TABLE 1. Main Phenotypic Changes in Inflammatory Neutrophils
Resting neutrophils Inflammatory neutrophils References
Increase in Ca2? mobilization
Release of granule molecules
Secretion of proinflammatory cytokines
Secretion of chemokines for
neutrophils and monocytes
Induction of monocyte and
Bone marrow and blood
[34, 35, 67]
[34, 35] (see Table 2)
Resting neutrophils recruited from reserve pools to infectious/inflammatory sites acquire the new phenotype of activated, inflammatory neutro-
Volume 87, January 2010
Journal of Leukocyte Biology 3
munity, IL-17 not only recruits and activates neutrophils but
also inflammatory monocytes/macrophages that are attracted
directly [107, 114, 115] or as a consequence of the induction
of secretion of CCL2 .
Besides proinflammatory cytokines, activated neutrophils
secrete CXC chemokines, primarily attracting neutrophils (in-
cluding CXCL8 and CXCL1/2/3), and CC chemokines, pri-
marily attracting monocytes (such as CCL2 and CCL3/4; Fig.
1, upper panel) [34, 35]. In the cross-talk with other cells, in-
flammatory neutrophils also use released granule molecules
for relevant direct and indirect immunomodulatory activities
[116, 117]. These include direct chemotaxis for neutrophils
and monocytes  (that amplify the activity of neutrophil-
secreted chemokines) and activation of monocytes and macro-
phages with enhancement of their phagocytic and antimicro-
bial abilities [119–121].
These networks of proinflammatory cytokines and chemo-
kines originate the clustering at infectious/inflammatory foci
of neutrophils, monocytes, macrophages, and DCs.
NEUTROPHILS AND MACROPHAGES
CLUSTERED AT INFECTIOUS FOCI
COOPERATE AS CENTRAL PLAYERS OF
Macrophage-neutrophil cooperation at the
The previous overview about the macrophage and neutro-
phil involvement in the modulation of immune responses to
infection shows that the two professional phagocytes cooper-
ate in the orchestration of the innate immunity as well as in
the translation between this initial response and adaptive
immunity. Regarding innate immunity, the cooperation be-
tween macrophages and neutrophil is based on the com-
mon expression of PRRs by both phagocytes ; the com-
mon secretion of proinflammatory cytokines and chemo-
kines (Table 2); and the common expression of some
cytokine and chemokine receptors (Table 2). This intercon-
nectivity between professional phagocytes creates several
feedback loops that amplify and sustain their clustering and
activation. The cooperation macrophage-neutrophil in the
orchestration of the adaptive immune response is based on
the common capacity to shuttle antigens to lymph nodes
, to regulate DC functions [43, 122], and to present an-
tigens directly to these cells .
Macrophage-neutrophil cooperation as an effector
One logical approach to assess the roles of neutrophils in
physiological and pathological situations is to use animal mod-
els lacking this phagocyte. As viable genetic mutants selectively
deficient in neutrophils are not available, and there are no
drugs for selective pharmacological induction of neutropenia,
antibody-mediated depletion of these phagocytes has been
used widely. The mAb RB6-8C5 has been used in many stud-
ies, but it is a problematic reagent. RB6-8C5 targets the anti-
gens Ly6G and Ly6C  expressed on neutrophils .
However, Ly6C (but not Ly6G) is also expressed on monocytes
. Thus, RB6-8C5 depletes neutrophils and monocytes when
injected at a high dose  but depletes neutrophils selec-
tively when administered in a single low dose (100 ?g or less)
[75, 125, 126]. This is the result of neutrophils being the ma-
jor target of RB6-8C5, as this mAb targets Ly6G mainly, which
is expressed almost uniquely on neutrophils . Moreover,
administration of RB6-8C5 should be done before the micro-
bial challenge, as RB6-8C5 treatment may induce pathological
side-effects if administered after microbial challenge ,
which may complicate the interpretation of the effects of in-
Another approach to assess the specific roles of each profes-
sional phagocyte would be through the use of genetically mod-
ified animals engineered to prevent the recruitment of each
phagocytic line selectively. However, the commonalities already
discussed between neutrophils and monocytes/macrophages
regarding expression of some chemokine receptors complicate
the assessment of the roles of each phagocyte line using mice
genetically lacking chemokine receptors.
TABLE 2. Main Neutrophil, Monocyte, and Macrophage Chemokines and Their Receptors in Inflammatory Settingsa
Produced by Expressed on
Name Macrophages Ref.Neutrophils Ref.Monocytes Ref.Name Neutrophils Ref.Monocytes Ref.
aAll of the indicated references report results obtained in vivo. Although CXC chemokines mainly attract neutrophils, and CC chemokines
mainly attract monocytes , a CXC chemokine may recruit monocytes, and a CC chemokine may recruit neutrophils, as receptors for CXC and
CC chemokines may be concomitantly expressed in neutrophils or monocytes as shown in this table. Moreover, CXC and CC chemokines may be
secreted by monocytes, macrophages, and neutrophils. This, as discussed in the main text, reflects a facet of the commonalities between neutro-
phils and monocytes/macrophages and makes questionable the use of genetically modified animals lacking CXC or CC receptors or deficient in
production of CXC or CC chemokines to assess the specific roles of each phagocyte.
Journal of Leukocyte Biology
Volume 87, January 2010
In conclusion, the closeness highlighted previously between
the two lines of professional phagocytes complicates the effi-
cacy of methods to deplete each of them selectively.
Macrophages extend the survival of recruited neutrophils at infec-
tious foci. The short lifespan of resting neutrophils (6–12 h) is
prolonged (to 24–48 h) after their recruitment to infectious/
inflammatory sites . This extension of neutrophil survival
is associated with the delayed entering in senescent apoptosis
 and is accompanied by prolongation of the functional
lifespan of these phagocytes [129, 130]. Thus, prolonged sur-
vival of recruited, activated neutrophils contributes to the en-
hancement of the defense against infection . However, as
will be discussed later, if not properly regulated, this survival
extension contributes to tissue damage-associated pathology
Factors that prolong survival of neutrophils recruited to in-
fectious/inflammatory sites include, besides some microbial
products, IL-1?, TNF-?, G-CSF, and GM-CSF [128, 132–134].
Macrophages participate in the secretion of those factors [13,
129, 135]. Therefore, macrophage-induced extension of neu-
trophil survival at infectious foci represents another modality
of macrophage-neutrophil cooperation.
Macrophage-neutrophil cooperation in protective immunity
against bacterial intracellular pathogens. Macrophages are the
preferred host cells for bacterial intracellular pathogens ,
and intramacrophage residence and multiplication are crucial
phases in the life cycle of those pathogens . When pro-
tective immunity ensues, macrophages turn into effectors of
pathogen clearance , so that macrophages are classically
considered the main professional phagocyte involved in the
control of this type of infection . However, several results
point to the cooperation of neutrophils in the elimination of
bacterial intracellular pathogens. The clustering at the infec-
tious foci of macrophages and neutrophils was described, for
example, in mycobacteriosis [139–143], in systemic  and
oral  listeriosis, in salmonellosis , and in legionello-
Depletion of neutrophils under conditions considered above
to induce adequate and selective neutropenia suggested neu-
trophil participation in the early innate defense mechanisms
against infection by bacterial intracellular pathogens such as
Listeria monocytogenes [147, 148], Legionella pneumophila ,
Francisella tularensis , Burkholderia pseudomallei , Chla-
mydia trachomatis , Salmonella enterica serovars Typhi-
murium , and Dublin .
Several studies using the mAb RB6-8C5 to assess the par-
ticipation of neutrophils in mycobacterial infections found
an early exacerbation of the infection (reviewed in ref.
). However, those studies used prolonged RB6-8C5 ad-
ministration of high doses, thus not conforming to the con-
ditions discussed above for the induction of adequate exper-
imental neutropenia. Protocols following the adequate con-
ditions are likely to be insufficient to induce the lasting
neutropenia necessary in the case of the slow-growing
pathogenic mycobacteria. Therefore, this approach may not
be adequate to evaluate the participation of neutrophils in
the protective innate immunity against mycobacteria. How-
ever, there are other data suggesting a role of neutrophils
in that immunity. An inverse relationship between periph-
eral blood neutrophil counts and risk of Mycobacterium tuber-
culosis infection was demonstrated in a large cohort of tu-
berculosis contacts . Moreover, that work found that
whole blood samples from healthy human donors have anti-
microbial activity against Mycobacterium bovis bacillus
Calmette-Guerin and M. tuberculosis, an activity that is neu-
trophil-associated, as it was decreased significantly by selec-
Figure 1. Schematic representation of the clustering and interactions
of neutrophils, monocytes, and macrophages at inflammatory sites of
infection by extracellular or intracellular pathogens. (Upper panel)
Resident macrophages that detect the presence of invading pathogens
(red rods) phagocytose them (A) and secrete chemokines, primarily
recruiting neutrophils (such as CXCL8 and CXCL1/2/3; large red
gradient) and monocytes (such as CCL2 and CCL3/4; large blue gra-
dient; see Table 2). Recruited neutrophils become activated (B; see
Table 1). Activated neutrophils complement the macrophage recruit-
ing of inflammatory phagocytes by attracting additional inflammatory
neutrophils (E) and monocytes (F) through the secretion of CXCL8
and CXCL1/2/3 (small red gradient) and CCL2 and CCL3/4 (small
blue gradient), respectively (see Table 2). Recruited monocytes
(C) give rise to inflammatory macrophages (D). (Lower panel) Infec-
tious focus with resident macrophages clustered with recruited inflam-
matory neutrophils, monocytes, and macrophages (same cell styles as
in upper panel). Effector mechanisms activated by phagocytes against
invading pathogens (red rods) include: phagocytosis by resident
(1) and inflammatory macrophages (2) and by recruited neutrophils
(3); infected macrophages ingest neutrophils (4) and released neutro-
phil granule proteins (5) to enhance their antimicrobial capacity; acti-
vated neutrophils release granules and antimicrobial granule pro-
teins that directly kill pathogens free in the extracellular space (6);
neutrophil extracellular traps kill pathogens free in the extracellu-
lar space (7).
Volume 87, January 2010
Journal of Leukocyte Biology 5
tive neutrophil depletion of the blood samples with anti-
CD15 antibodies. Other data favoring the view that neutro-
phils participate in the innate defense against mycobacterial
infections will be discussed below.
The cooperation of neutrophils in the innate immunity
against bacterial intracellular pathogens may involve immuno-
modulatory [151, 154, 156] and/or effector activities, which
can use different mechanisms (Fig. 1, lower panel) as dis-
Neutrophils enhance macrophage antimicrobial abilities. As the mac-
rophage is the primary effector of antimicrobial activity against
those pathogens, an efficient strategy in the participation of
neutrophils as effectors against those agents would be through
supplying the macrophage with potent antimicrobial neutro-
phil granule molecules lacking in the macrophage. This would
reinforce the limited antimicrobial capacity of macrophages.
A mechanism of macrophage-neutrophil cooperation based
on the transfer to infected macrophages of neutrophil antimi-
crobial molecules was proposed initially in a murine model of
experimental mycobacteriosis . That study showed that in
mycobacteria-infected sites, where macrophages and neutro-
phils cluster, including peritoneal cavity, foot-pad s.c. tissue,
liver, and lung, macrophages ingested neutrophils, and lacto-
ferrin was found within macrophages and predominantly in
those infected with mycobacteria  (Fig. 1, lower panel,
4). Additionally, that study showed that the transfer of neutro-
phil granule molecules to cultured macrophages infected with
Mycobacterium avium or Mycobacterium microti enhanced the anti-
mycobacterial capacity of macrophages against those patho-
gens. This observation led to the novel concept that neutrophils
participate in the macrophage-mediated control of mycobacterial
infections by supplying potent antimicrobial molecules lacking in
macrophages . This mechanism of macrophage-neutrophil
cooperation was suggested later for infections by M. tuberculosis
 and L. pneumophila . Moreover, a role in that mecha-
nism of neutrophil HNP-1 and MPO in infections by M. tuberculo-
sis and M. avium was suggested [157, 159–161].
Several data support that cooperative mechanism and sug-
gest that it operates in other infections by bacterial intram-
acrophage pathogens besides mycobacteria. On the one
hand, neutrophil granule molecules are known to be micro-
bicidal in vitro against several intracellular pathogens [155,
157, 159, 161–164]. On the other hand, those molecules
were found to be taken avidly by macrophages in vitro and
to enhance the antimicrobial activity against several intram-
acrophage pathogens [158, 161, 165–170]. Additionally,
neutrophil molecules are detected in vivo within macro-
phages at infectious sites resulting from intramacrophage
bacterial pathogens [139, 171].
Recent results using human macrophages and neutrophils
 confirmed and extended those initial observations by
showing that phagocytosis of apoptotic neutrophils by macro-
phages infected with M. tuberculosis resulted in the transfer of
the antimicrobial peptide HNP-1 to the compartments in
which mycobacteria reside within macrophages; this transfer
was accompanied by a dose-dependent reduction in the via-
bility of intramacrophage M. tuberculosis. Uptake of purified
granules alone also decreased growth of intracellular myco-
The above data indicate that at infectious/inflammatory
sites, macrophages may acquire neutrophil antimicrobial mole-
cules through phagocytosis of neutrophils (Fig. 1, lower panel,
4) or intake of neutrophil granules (Fig. 1, lower panel, 5).
Macrophages are the main scavenger of senescent, apoptotic
neutrophils , which provides one mechanism of acquisi-
tion of neutrophil molecules. Macrophages with phagocytosed
neutrophils are constantly seen at infectious foci, and its oc-
currence is maintained as long as the neutrophil influx per-
sists . This phagocytosis is associated to an active anti-
inflammatory response in macrophages (reviewed in ref. ).
Phagocytosis of M. tuberculosis by neutrophils in vitro in-
duces rapid apoptosis of these phagocytes , and phago-
cytosis by macrophages of mycobacterium-infected apoptos-
ing neutrophils, instead of inducing an anti-inflammatory
response, activates macrophages [173, 174]. Therefore,
phagocytosis by macrophages of M. tuberculosis-infected apo-
ptotic neutrophils may represent an important host defense
mechanism leading to the enhancement of the antimicro-
bial activity of macrophages.
The above data indicate that phagocytosis of apoptosing
neutrophils by macrophages is not a mechanism solely in-
volved in the removal of senescent neutrophils but addition-
ally, may be used to procure the acquisition of additional anti-
microbial molecules to help fight intramacrophage pathogens.
It is expectable, therefore, that macrophages would phagocy-
tose not only apoptosing neutrophils as a scavenging process
but also viable neutrophils as a cooperative antimicrobial
mechanism. This implies that nonapoptosing neutrophils
would be able to express surface “eat-me” signals that promote
their uptake by macrophages. One major eat-me signal on the
surface of apoptosing cells is externalized PS , and it has
been reported that PS exposure on neutrophils leading to
phagocytic recognition and removal by macrophages can oc-
cur independently of apoptosis following neutrophil activation
Neutrophil granules and antimicrobial granule proteins are
known to be released in a controlled manner at infectious
sites as a result of degranulation associated to activation .
The activation discussed previously of macrophages and en-
hancement of their phagocytic activity by released neutrophil
granule proteins at infectious/inflammatory sites [165, 179]
represent other modalities of neutrophil-macrophage coopera-
tion, boosting the antimicrobial innate immune response.
The above data suggest that when bacterial intracellular
pathogens invade macrophages, these phagocytes call neutro-
phils to help and use the highly potent and abundant antimi-
crobial molecules of this phagocyte to enhance their limited
antimicrobial capacity. This is a safe way of macrophages using
powerful microbicidal molecules without the risk of perma-
nently carrying them.
Direct effector activity of neutrophils toward intracellular pathogens.
Intracellular pathogens can be exposed to the direct effec-
tor activity of the neutrophil when they are outside of their
host cell. This extracellular location occurs when the patho-
gens transit from one host cell to the next; additionally,
Journal of Leukocyte Biology
Volume 87, January 2010
some of them may have a phase of extracellular residence
and multiplication in the host .
Direct neutrophil effector antibacterial activity against
free intracellular pathogens may operate through phagocy-
tosis (Fig. 1, lower panel, 3), release of granule antimicro-
bial molecules (Fig. 1, lower panel, 6), or use of extracellu-
lar traps  (Fig. 1, lower panel, 7). Bacterial intracellu-
lar pathogens can be seen within neutrophils in vivo, as
reported in infections by Mycobacteria [40, 139, 181], Salmo-
nella [182, 183], L. monocytogenes [184, 185], and L. pneumo-
phila [146, 186]. Several studies show that many, but not all
[148, 181, 183, 187], intracellular pathogens can survive
within neutrophils (reviewed in ref. ), suggesting that
a direct effector activity of these phagocytes would not be a
widespread host defense mechanism in infections by those
pathogens, in contrast to infections by bacterial extracellu-
lar pathogens .
Neutrophils transfer intracellular pathogens to macrophages. Neu-
trophils that ingested intracellular pathogens can be phagocy-
tosed by macrophages coexisting at the same infectious site.
This ingestion will transfer to macrophages the pathogens ini-
tially within neutrophils [139, 143, 171, 184, 189]. An outcome
of that transfer that represents another example of coopera-
tion between macrophages and neutrophils in the innate de-
fense against infection is the elimination within the macro-
phage of the transferred pathogen with the participation of
the antimicrobial mechanisms of the macrophage and of the
Macrophage-neutrophil cooperation against bacterial extracellu-
lar pathogens. As in the case of intracellular pathogens, the
recruitment of neutrophils and monocytes to sites of infec-
tion by bacterial extracellular agents [79, 190, 191] is
largely a result of neutrophil- and monocyte-attracting che-
mokines secreted by resident macrophages following the
recognition of the invading pathogens [192–194]. Human
macrophages infected in vitro with Streptococcus pyogenes se-
crete the chemokine CXCL8, primarily attracting neutro-
phils, and the chemokines CCL2 and CCL3, primarily at-
tracting monocytes .
Although neutrophils are the main effectors in innate im-
munity against bacterial extracellular pathogens  through
phagocytosis  (Fig. 1, lower panel, 3), release of granule
antimicrobial molecules  (Fig. 1, lower panel, 6), or use of
extracellular traps  (Fig. 1, lower panel, 7), the participa-
tion of monocytes/macrophages in cooperation with neutro-
phils has been shown to be relevant for the early control of
those pathogens [194, 197]. Macrophage depletion in mice
increased susceptibility to S. pyogenes  and Staphylococcus
aureus . One modality of this cooperation depends on
the macrophage direct effector activity through phagocytosis and
killing of the extracellular parasite  (Fig. 1, lower panel, 1
and 2). The observation that the antimicrobial activity of cultured
macrophages against ingested Escherichia coli  or Pseudomonas
aeruginosa  is enhanced following the acquisition by the in-
fected macrophages of neutrophil MPO suggests that the mecha-
nism of macrophage-neutrophil cooperation, based on the trans-
fer of neutrophil antimicrobial molecules to infected macro-
phages, may operate in infections by bacterial extracellular
pathogens as well.
Macrophage-neutrophil cooperation against eukaryotic pathogens.
Some results suggest the occurrence of a cooperative participa-
tion of macrophages and neutrophils also in infections by pro-
tozoans such as Trypanosoma cruzi , Leishmania major [77,
200], and Cryptosporidium parvum  and fungi such as As-
pergillus fumigatus , Histoplasma capsulatum , and
Candida albicans [168, 203].
The antimicrobial activity of macrophages infected
in vitro with T. cruzi , C. albicans [168, 169], or H. cap-
sulatum  is enhanced by the acquisition of neutrophil
lactoferrin, MPO, or HNP-1, respectively. This suggests that
the mechanism of macrophage-neutrophil cooperation
based on the transfer to infected macrophages of neutro-
phil antimicrobial molecules may also operate in those in-
Macrophages and neutrophils cluster in the inflammatory
exudate produced early after i.p. infection with Toxoplasma
gondii; the macrophage is the major host cell for the para-
site in this exudate . Both phagocytes have been impli-
cated in the innate defense against the parasite (reviewed in
ref. ). However, this implication is based on controver-
sial data, as the studies with mice made neutropenic with
RB6-8C5 used protocols of administration of that mAb that
do not conform to the conditions discussed already to
achieve an adequate neutrophil depletion. However, al-
though not definitive, the observations that in mice geneti-
cally deficient in CXCR2  or IL-17R , infected
with virulent T. gondii, the defective early neutrophil re-
cruitment is associated with higher susceptibility, suggest
that neutrophils participate with macrophages in the innate
defense against that pathogen.
COOPERATION IN THE RESOLUTION OF
Upon effective control of the infection, the presence of poten-
tially dangerous neutrophils at infectious/inflammatory foci
can be terminated quickly, as these phagocytes are short-lived
cells, which when senescent, enter apoptosis and are removed
by macrophages before lysis and associated tissue damage [65,
172]. Indeed, although the survival of neutrophils is pro-
longed after recruitment to infectious sites, they ultimately un-
dergo apoptosis and are removed mainly by scavenger macro-
Usually, phagocytosis of apoptosing neutrophils by macro-
phages leads to resolution of inflammation with restitution
of tissue homeostasis soon after neutrophils have accom-
plished their task . Appropriately, this phagocytosis is
associated to an active anti-inflammatory response in macro-
phages by induction of TGF-? and IL-10 production (re-
viewed in ref. ). When the scavenging capacity of mac-
rophages is overwhelmed, neutrophils may function as a
backup system ; monocytes also phagocytose apoptosing
neutrophils . Senescent monocytes and macrophages
also enter apoptosis and are removed by scavengers, mainly
Volume 87, January 2010
Journal of Leukocyte Biology 7
macrophages [68, 209]. Therefore, besides their effector
and modulator activities, the members of the phagocyte sys-
tem accumulate the function of scavengers of the senescent
cells of the system, thus contributing to its safer operation.
These results indicate another modality of macrophage-neu-
Infection-associated cell and tissue damage involves a synergis-
tic interaction among many microbial- and host-derived proin-
flammatory agonists [210–212]. Within the context of this
review, the phagocyte-associated tissue damaging will be high-
lighted. Protective immunity is only beneficial if well con-
tained. Phagocyte accumulation at infectious/inflammatory
foci may contribute to pathology through the relevant proin-
flammatory and tissue-damaging effects of these cytotoxic
phagocytes (reviewed in refs. [65, 213]).
As discussed elsewhere [210, 214, 215], leukocyte-inflicted
tissue damage involves a network of marked complexity, re-
quiring the cross-talk among different cell types, mediators,
cytotoxic agents, and their respective inhibitors. The participa-
tion of professional phagocytes in infection-associated tissue
injury may involve the direct, deleterious effects of excessive
activity of phagocytic cytotoxic molecules released during un-
controlled neutrophil degranulation  or as a consequence
of nonprevented neutrophil lysis (reviewed in ref. ).
Phagocyte-associated tissue injury is mediated by the microbici-
dal molecules that participate in antimicrobial defense, includ-
ing ROS, RNS, peroxynitrite, and cationic proteins [210, 216].
Proinflammatory cytokines (such as IL-1?, TNF-?, and IL-17)
and chemokines are involved in excessive inflammatory tissue
damage associated to infection. A likely indirect mechanism
may also participate, whereby phagocyte granule antimicrobial
proteins, in addition to their killing effects as a result of per-
meabilization of microbial membranes, also activate nascent
autolytic wall enzymes; this activation will lead to bacteriolysis
with release of the highly phlogistic, LPS, lipoteichoic acid,
and peptidoglycan envelope components . Regarding the
direct damaging activity of phagocytes, it is relevant that neu-
trophils are particularly potentially cytotoxic as a result of their
powerful oxidative, enzymatic, and peptidic antimicrobial
mechanisms [19, 65] and that the prolonged neutrophil sur-
vival at infectious sites may contribute to tissue injury. Addi-
tionally, the more limited antimicrobial/phlogistic activities of
macrophages may participate in the infection/inflammation-
associated tissue damage . This indicates that besides the
cooperation in protective, beneficial defense mechanisms,
macrophage-neutrophil cooperation also participates in the
infection/inflammation-associated pathogenesis. In other
words, macrophage-neutrophil cooperation might have two
MACROPHAGES AND NEUTROPHILS ARE
TARGETED BY MICROBIAL
So far, this review has been centered on the host innate im-
mune phagocytic mechanisms that control microbial infec-
tions efficiently. However, the other possible outcome of
the host/parasite interaction results in the defeat of the
host immunity by the pathogenicity factors of the infectious
As the pathogenic success of extracellular pathogens is
largely dependent on resistance to the effector mechanisms of
phagocytes, mainly neutrophils [79, 138], the major virulence
factors of those pathogens include means to prevent phagocy-
tosis. In accordance with the concept highlighted in this re-
view are the observations showing that the same molecule is
able to attack neutrophils and macrophages in several bacte-
rial pathogens; this is the case of toxins from the highly viru-
lent P. aeruginosa , Photobacterium damselae subspecies pisci-
cida , Yersinia pestis , and S. aureus , among
Intracellular bacterial pathogens are dependent on living
macrophage host cells and many of their functions ,
and they have evolved mechanisms to evade macrophage
antimicrobial mechanisms . In accordance with the
participation of neutrophils in the innate host defense
against intracellular bacterial pathogens, one relevant viru-
lence factor of these pathogens is to attack neutrophils
[213, 221, 222]. Significant examples are Brucella abortus
, B. pseudomallei , Burkholderia cepacia , F.
tularensis , C. trachomatis , Chlamydia pneumoniae
, M. tuberculosis , Mycobacterium ulcerans , L.
monocytogenes , Legionella micdadei, L. pneumophila ,
and Haemophilus somnus .
MACROPHAGES AND NEUTROPHILS
FUNCTION AS PARTNERS IN A MYELOID
Following the Ludwig Aschoff concept, cellular systems have
been created based on the sharing of a set of features, mainly
origin and function. Based on this criterion, the mononuclear
phagocyte system  was created as a system of dedicated
phagocytic cells, grouping macrophages and their precur-
sors but excluding neutrophils. This exclusion was based on
the argument that “Although polymorphonuclear phago-
cytes are mononuclear too, they belong to another cell line
because of their different origin and divergent kinetic and
functional behavior.” .
However, present knowledge about the biology of phago-
cytes does not justify the maintenance of neutrophils out-
side of a system of dedicated phagocytes. The concept of
the mononuclear phagocyte system was proposed at a con-
ference about mononuclear phagocytes held in 1969 . At
the time, details of myelogenesis were not known, and neu-
trophils were considered to belong to another cell line and
to be a terminally differentiated phagocytic effector that
releases preformed mediators and kills pathogens but is de-
Journal of Leukocyte Biology
Volume 87, January 2010
void of transcriptional activities. However, the advances in
the knowledge of neutrophil biology helped to change that
traditional view, and neutrophils emerged progressively as
immune cells with important roles in the regulation of im-
mune responses. Moreover, and as highlighted here, neutro-
phils and macrophages have a common origin, share several
essential capabilities, and cooperate in important immune
activities. Finally, two functional criteria that were taken
into consideration to select cells to be grouped in the
mononuclear phagocyte system, namely pinocytosis and the
ability to attach firmly to a glass surface, are now known to
be exhibited by neutrophils as well [228, 229]. Thus, the
view that neutrophils should be included with the members
of the mononuclear phagocyte system (monocytes, macro-
phages, and DCs) in a broader myeloid phagocyte system is
justified. Because of their crucial phagocytic and antimicro-
bial capabilities, neutrophils and macrophages are the effec-
tor arms of this revised system.
The data here highlighted indicate that the common origin
and the specialization during differentiation endow macro-
phages and neutrophils with overlapping and complementary
abilities, which they use in a concerted innate immune attack
strategy to fight infection. That strategy is based on several
modalities of cooperation between the two professional phago-
cytes (summarized in Table 3).
When intracellular or extracellular pathogens invade
mammal host tissues, resident macrophages detect the
pathogen and recruit neutrophils from reserve pools to as-
sist them in the antimicrobial effector mechanisms. Indeed,
although the phagocytes with more important roles against
intracellular and extracellular pathogens are macrophages
and neutrophils, respectively, the two professional phago-
cytes operate in concert in both infectious situations: Neu-
trophils help macrophages to fight intracellular pathogens,
and macrophages assist neutrophils in the defense against
Starting from a common myeloid precursor in the bone
marrow, which provides many overlapping characteristics,
macrophages and neutrophils split during differentiation,
specialize with the acquisition of distinctive features that
complement the shared properties, and finally, join at the
infectious foci for a cooperative antimicrobial defense: (i)
Resident macrophages are long-lived cells strategically dis-
tributed in all body territories as sentinels of microbial in-
vaders and conveniently, for a tissue-resident cell, are lim-
ited in cytotoxic mechanisms at the cost of some antimicro-
bial activity. (ii) Neutrophils are more microbicidal as a
result of expression of high amounts of powerful and cyto-
toxic antimicrobial molecules; consequently, they are poten-
tially dangerous phagocytes strategically stored as reserve
pools during steady-state conditions as resting cells in bone
marrow and blood, activated and used only in emergency
situations, when, where, and while needed. (iii) At the be-
ginning of the infectious process, tissue macrophages that
detect invading pathogens recruit monocytes, which mature
into inflammatory macrophages, and neutrophils. (iv) The
immunomodulatory abilities of attracted neutrophils com-
plement macrophages in the recruitment of additional
phagocytes; these redundant recruitment circuits lead to the
clustering of macrophages and high numbers of neutrophils
at infectious sites. (v) In these sites, macrophages partici-
pate in the extension of neutrophil survival and macro-
phages and neutrophils interact and cooperate at infectious
foci for an effective innate antimicrobial immunity through
effector mechanisms as specialized partners of a myeloid
phagocyte system; additionally, the two phagocytes cooper-
ate in immunomodulatory activities, including in the or-
chestration of innate and adaptive immunities. (vi) Upon
effective control of the infection, the presence of potentially
dangerous neutrophils at infectious/inflammatory foci is
terminated quickly through the removal of senescent/apo-
ptotic neutrophils by macrophages before lysis and associ-
ated tissue damage.
The specialization behind the neutrophil and monocyte/
macrophage lineage specification is the basis of an advanta-
TABLE 3. Aspects of the Cooperation between Macrophages and Neutrophils As Effectors and Modulators in Protective
Antimicrobial Innate Immunity
Macrophages and neutrophils participate in the orchestration of innate immunity:
Neutrophils and macrophages express PRRs.
Macrophages and neutrophils secrete proinflammatory cytokines.
Macrophages and neutrophils recruit neutrophils and monocytes to infectious sites.
Neutrophils activate macrophages, and macrophages activate neutrophils.
Macrophages and neutrophils cooperate as effectors of antimicrobial innate immunity:
Neutrophils and macrophages phagocytose and kill microbial pathogens.
Neutrophils enhance the phagocytic ability of macrophages.
Neutrophils supplement macrophages with molecules that enhance macrophage antimicrobial capacities.
Neutrophils transfer to macrophages intracellular pathogens.
Macrophages and neutrophils cooperate in the resolution of infectious inflammation.
Macrophages and neutrophils participate in the translation of innate to adaptive immunity.
(see Table 2)
[49, 172, 208]
[17, 47, 156]
Volume 87, January 2010
Journal of Leukocyte Biology 9
geous, cooperative innate immune attack strategy that al-
lows the efficient and safe use in antimicrobial mechanisms
of powerful and dangerous microbicidal molecules. To
achieve this, the two mammalian professional phagocytes
combine overlapping and complementary capabilities and
work in concert as two specialized effectors and modulators
of a myeloid phagocyte system.
I am grateful to Joa ˜o Pedro Pereira, Margarida C. Neves, Jorge
Pedrosa, and A. Gil Castro for helpful discussions, to Anabela
Costa for editorial assistance, and to Bernardo Gama for the
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myelopoiesis ? phagocytosis ? chemotaxis ? antimicrobial mecha-
nisms ? pathogenicity mechanisms
Journal of Leukocyte Biology
Volume 87, January 2010