Jurnal Deno PDF

Macrophage defences against respiratory
tract infections
S B Gordon*,† and R C Read†

*Wellcome Trust Research Laboratories, Universities of Malawi and Liverpool (UK), Queen
Elizabeth Central Hospital, Blantyre, Malawi
†
Division of Genomic Medicine, University of Sheffield Medical School, Royal Hallamshire
Hospital, Sheffield, UK
Pulmonary macrophages with a key role in defence against respiratory infection

are a heterogeneous family of cells with phagocytic, antigen processing and
immunomodulatory functions. Macrophages are important in both innate and
acquired immunity in the respiratory tract, and have a role in lung defence
against viruses, bacteria, mycobacteria and fungi. Interactions of pathogens
with lung macrophages is strongly influenced by soluble immune components
including complement, collectins and immunoglobulins. Macrophage function
can be modulated by cytokines, environmental exposures, recent and chronic
infection including HIV infection, drug therapy and gene transfer.
For effective respiration large volumes of ambient air must flow as close as
possible to circulating erythrocytes. This engenders a substantial infective
risk as airborne pathogens regularly ingress deep into the body and within
1 µm of warm circulating blood. To counter this risk, effective anti-
infective mechanisms defend the gas-exchanging areas. This function is
complex, however, as a large allergen load is also inspired with each breath
and even moderate inflammation of the lung parenchyma is a threat to the
host because of impairment of effective gas transfer. Macrophages have a
pivotal role in immune surveillance of the respiratory tract, appropriate
initiation of anti-infective inflammation and regulation of potentially
harmful inflammatory responses.
Origin and types of respiratory tract macrophages

Correspondence to:
Origin of lung macrophages
Dr R C Read, Division of
Genomic Medicine, All macrophages originate from precursor cells in haemopoietic organs and
University of Sheffield
Medical School, Royal
gain access to the respiratory tract via blood and lymph. Marrow promono-
Hallamshire Hospital, cytes mature and enter the circulation as monocytes. Monocytes leave the
Sheffield S10 2RX, UK circulation and develop into extravascular mature tissue macrophages that
British Medical Bulletin 2002;61: 45–61  The British Council 2002
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Childhood respiratory diseases
have varied phenotype according to the location, function and state of

activation of the cell1.
Macrophages play a role in early fetal lung development by phagocytosis
of apoptotic cells. Monocytes that enter the mature lung differentiate into
macrophages under the influence of local factors (alveolar type 2 cells,
bronchial epithelium, cytokines, surfactant); the major resident macro-
phages responsible for lung defence are alveolar macrophages and den-
dritic cells. Other lung macrophages include pleural, interstitial and intra-
vascular macrophages, but these are reviewed elsewhere2, as are the unique
properties of macrophages in the neonatal lung3.
Alveolar macrophages
Alveolar macrophages (AM) form 95% of the cell burden in broncho-

alveolar lavage, the remainder being lymphocytes. AM are resident lung
phagocytes which express high densities of immunoglobulin receptor (fcR),
complement receptor (CR), mannose receptor (MR) and several types of
scavenger receptors4 to facilitate phagocytosis of opsonised and non-
opsonised particles. The Toll-like receptor (TLR) group has structural
homology to the primitive immune system in Drosophila and TLR2
receptors have been recently shown to mediate innate responses to Myco-
bacterium tuberculosis and Streptococcus pneumoniae in human AM5.
Like other tissue macrophages, alveolar macrophages have a very active
plasma membrane. In addition to receptor-mediated phagocytosis and
endocytosis, they internalise particulate material, surfactant and patho-
gens by a range of receptor-independent plasma membrane ruffling and
folding mechanisms, and can recycle the entire plasma membrane every
30 min as a result of endosomal trafficking.
Alveolar macrophages are active producers of cytokines and leukotrienes,
and have important pro- and anti-inflammatory roles in the alveolus.
Approximately one AM is found in each alveolus, but they can migrate
between acini via the pores of Kohn.
AM are relatively poor antigen-presenting cells, and have been shown to
down-regulate T cell responses to antigen6,7.
Dendritic cells
Dendritic cells (DC) share a common precursor with AM but

differentiate in a different location (airway submucosa) to form cells
with a distinct morphology, receptor expression, antigen processing
capacity and function8. Dendritic cells have long finger-like processes
and form a meshwork in the submucosa of the nasopharynx, trachea
and bronchial tree akin to the Langerhan’s cells of the skin.
46 British Medical Bulletin 2002;61

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Macrophage defences against respiratory tract infections
DC are extremely efficient antigen-presenting cells but weak phago-

cytes. They bind antigen, migrate to the regional lymph node and
present the antigen there to produce brisk T-cell activation (at a distance
from the delicate alveolar surface), relevant in T-cell mediated immunity
and pulmonary humoral responses to infection.
Monocytes
Circulating monocytes, like neutrophils and lymphocytes, form an
important reserve component of pulmonary defence against infection
that can be rapidly recruited when necessary. Inflammation in the alveoli
causes increased vascular permeability with extravasation of plasma and
blood cells including neutrophils (classically ‘red hepatisation’). This is
followed after an interval by ‘gray hepatisation’, a phase dominated by
monocyte phagocytosis of cell debris and inflammatory products.
Monocytes are known to play important roles in T-cell and macrophage
activation by cytokine signalling9.
Overview of macrophages in respiratory tract defences
Innate and acquired immunity
Immune responses can be subdivided into innate and acquired systems

and macrophages in the respiratory tract play important roles in both.
Innate immunity
Macrophages can initiate phagocytosis with or without opsonisation with
complement and collectins, and subsequently release cytokines and other
products which orchestrate host cellular defence. Products released include
IL-12 (activates NK cells) and LTB4 (recruitment of neutrophils via IL-8
secretion, decreased macrophage apoptosis, increased CR expression),
toxic oxygen species (O2–, H2O2), T-cell stimulatory and pro-inflammatory
cytokines (TNF-α, IL-1) and antibacterial products such as lactoferrin
(iron binding), lysozyme and SLPI. It should be noted, however, that
alveolar epithelium and lymphocytes are also major sources of pro-
inflammatory cytokines.
Bacteria, bound to the surface of macrophages, are rapidly internalised
into phagosomes, which engage with endosomal traffic and gradually
acquire the characteristics of terminal phagolysosomes, an event con-
comitant with death of the microbe. Phagolysosomes can be identified by
the presence of a number of glycolipids within the compartment membrane,
for example lysosome-associated membrane protein (LAMP; see Fig. 1).
British Medical Bulletin 2002;61 47

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Fig. 1 Immunofluorescence of human alveolar macrophages infected with Strep.

pneumoniae. The two panels are identical fields of view of cells after 80 min of interaction
at 37°C. (A) Through the UV filter, DAPI-labelled bacteria are shown in association with
macrophages. (B) Through the triple filter, some pneumococci are seen to fluoresce green
because they are accessible to FITC-labelled antipneumococcal antibody (larger arrow). This
indicates that they have not been internalized. Other pneumococci, however, do not
fluoresce green, and some are seen to co-localize with the CY-3-immunolabelled LAMP,
which forms red rings around them, indicating that they are within late endosomal or
lysosomal compartments (smaller arrow). Reproduced from Gordon et al32 with permission.

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Some pathogens (e.g. Legionella spp. and Mycobacteria spp.) can frustrate
phagolysosomal processing, either by resistance to the phagosome contents
or by escape from the phagosome into the cytosol.
Toll-like receptors (TLRs) on the surface of macrophages (and other
cells) are a family of receptors which can recognise primitive repetitive
microbial patterns and subsequently transduce a number of responses,
including cytokine release, antimicrobial peptide production and apo-
ptosis. Each family member recognises a restricted repertoire of microbial
pattern molecules (e.g. TLR4 recognises LPS, TLR2 recognises lipo-
peptides, TLR 5 recognises flagellin). For reviews, see Aderem and
Ulevitch10 and elsewhere in this issue.
Acquired immunity
Cells (macrophages, dendritic cells and lymphocytes) co-operate by means
of cytokine signals9 and orchestrate development of cell-mediated
immunity consisting of delayed-type hypersensitivity and cytotoxic T cells.
Antigen presentation by macrophages is critical to successful development
of both cell-mediated and humoral immunity.
Anatomical location and macrophage specialisation
Macrophages are located at points within the respiratory tract at which they
are likely to be maximally effective. Air drawn through the nose is filtered,
warmed and humidified in transit. In addition, airflow is slowed down to
the extent that large (> 10 µm diameter) particles are deposited in the nose
and throat where they adhere to mucous and are coughed, sneezed or
swallowed away from the respiratory tract11. Further air slowing and
particle deposition occurs at each of the approximately 18 airway bifur-
cations between the trachea and the alveoli. As a result, large particles are
deposited predominantly in the upper airways, and only particles of less
than 5 µm diameter are deposited in the alveoli. Thus, in the normal
respiratory tract, bacteria are deposited in areas where a thick mucous layer
and effective ciliary function, together with the cough reflex, form the
primary defence. The macrophage defence in these regions consists of
dendritic cells found in the submucosa where they are important in antigen
presentation and development of an acquired immune response when the
primary defence fails.
In the alveoli, however, smaller particles including pathogens are
widely dispersed onto an epithelium that is only protected by a thin layer
of alveolar lining fluid. Here, pathogens encounter AM capable of rapid
phagocytosis and killing. AM (rather than DC) are, therefore, part of the
primary defence mechanism here and to enhance phagocytosis, the alveolar
lining fluid contains locally produced IgA, IgG, complement, surfactant

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and collectins. These opsonins bind to the pathogen and to fcγ receptors,
fcα receptors, CR and MR on alveolar macrophages. In addition, alveolar
lining fluid contains secreted AM products of the innate immune response
(see above). AM have poor antigen presenting function, which is appro-
priate in this anatomical location as cell-mediated immune responses in the
alveoli cause pneumonitis as seen in inflammatory lung diseases (e.g.
sarcoidosis). In fact, AM even suppress the antigen presenting function of
DC near the alveolus, presumably for this reason12.
Compartmentalisation of the immune response
Animal studies have shown that both acute cytokine responses and acquired
antibody responses in the lung are localised to the challenged segment or
lobe of lung in experimental conditions13, which illustrates the remarkable
ability of lung defences to limit the extent of inflammation. Recent work has
shown that cytokine release is confined to the inflamed area until control of
the infection is lost and bacteraemia supervenes14.
Macrophage defences against viruses

Upper respiratory tract infections with viruses are common because large
airborne droplets deposit in the upper airway. The establishment of an
infection is dependent on inoculum size and host factors (genetics,
mechanical defences, cytokine milieu, state of airway cellular activation
and prior immunity). Most infections are subclinical but illness can range
in severity from acute self-limiting illnesses to systemic viraemia. The
pattern which occurs is dependent on viral factors (fusion with host cells,
replication rate) and host factors (innate immune mechanisms, adaptive
response timing, pre-existing lung disease, e.g. asthma). These are the
subjects of other chapters in this volume and will not be dealt with further
here. In this section, we will focus on the role of the macrophage in two
diametrically opposed conditions – acute self-limiting RSV infection and
chronic HIV disease.
Respiratory syncitial virus (RSV) – a battle often won
Macrophages, specifically dendritic cells, play a central role in defence

against RSV. When RSV infects the respiratory epithelium, the integrity of
this barrier is lost and virus antigens can be internalised by DC. In a murine
model, it has been shown that dendritic cells migrate to the regional lymph
node and participate (by antigen presentation and cytokine production) in

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activation of epitope-specific T cells15. These T-cells migrate back to the

inflammatory site under the influence of chemotactic gradients and
effect T-cell mediated virus killing16. In addition, antigen presentation by
DC facilitates the activation of B-cells to produce specific immuno-
globulin. B-cells migrate back to the respiratory epithelium and produce
virucidal antibody. Virus-specific antibody is detectable 3–5 days after
infection, but sustained effective serum antibody levels are not achieved
until 14–28 days after infection. Re-infection of the respiratory mucosa
is generally not possible (in animal models) until more than 9 months
after the initial infection due to the persistence of antibody17.
Human immunodeficiency virus (HIV) – a battle often lost
Infection with HIV usually involves macrophage-tropic strains. The virus

becomes T-cell-tropic late in disease. The lung becomes involved soon after
natural infection as early viraemia exposes activated, CD4+ tissue
macrophages in the lung to free virus. Macrophages in the lung are very
susceptible to HIV infection, but relatively resistant to the cytopathic
effects of the virus18. AM, therefore, become HIV infected in large numbers
and free virus is detectable in broncho-alveolar lavage fluid. Circulating
monocytes, on the other hand, are relatively resistant to infection until
activated in the periphery. Bacterial infection is known to increase the
susceptibility of AM to HIV infection19, probably by up-regulation of CD4
and chemokine receptors (co-receptors for HIV infection). Initially, AM
were described as having an unusually high load of HIV virus that
correlated with clinical status20. There are methodological complexities
that make determination of viral load and infection in AM hard to
measure, however, and recent work suggests that the HIV load in AM is
similar to that in other macrophage populations21.
HIV infection in the lung produces complex effects22. The disease itself
results in CD8+ lymphocytosis and a polyclonal increase in IgG in
broncho-alveolar lavage. The increase in lymphocyte numbers is thought
to reflect an appropriate cytotoxic response to the presence of HIV in
the lung. The inflammation produced results in a persistent drop in
pulmonary function23. The polyclonal increase in IgG is thought to be
ineffective as decreased percentages of pathogen specific antibody are
seen compared to HIV negative subjects following acute pneumococcal
infection, and susceptibility to bacterial and other infections is markedly
increased, as reviewed elsewhere in this issue.
HIV infects and affects lung macrophages. The AM functions altered by
HIV include receptor expression24, activation25, cytokine production18,
accessory cell function26, phagocytosis and apoptosis of alveolar macro-
phages. For example, mannose receptor up-regulation has been associated

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with increased susceptibility to M. tuberculosis by a surfactant A dependent

mechanism. Almost all cytokines studied have been shown to be increased
in HIV infection. Increased production of IL-6 may result in the observed
increase in broncho-alveolar lavage levels of IgG. Phagocytosis and killing
of Cryptococcus neoformans27 and Pneumocystis carinii28 have been seen to
be impaired in AM from HIV infected subjects. No impairment of
phagocytosis or killing of Staphylococcus aureus29 or Streptococcus
pneumoniae30 is observed.
Macrophage defences against bacteria

Streptococcus pneumoniae
Strep. pneumoniae is the most common cause of community acquired

pneumonia. The basic paradigm of infection is that asymptomatic
colonisation of the nasopharynx is achieved by expression of specialised
virulence factors such as surface binding proteins and capsular
polysaccharide by the bacteria. Infected droplets of nasopharyngeal
secretions are then inhaled. Normally, these are dealt with either by
bronchial or alveolar defences. On some occasions, however, local
infection of the lung parenchyma occurs which may either resolve
following a local inflammatory response or progress to bacteraemia31.
Numerous animal studies of bacterial clearance have shown that
infection is dependent on inoculum size and the host levels of capsular
specific antigen11. Studies of human alveolar macrophages have
consistently shown very low rates of bacterial ingestion and killing in
vitro even in the presence of optimal opsonisation. Recent work in our
laboratory has shown that binding and internalisation of Strep.
pneumoniae by human AM are dependent on opsonisation32. Binding of
opsonised bacteria by AM was halved by the use of opsonising serum
from which immunoglobulin had been adsorbed. Ig-depleted serum still
produced twice as much bacterial binding as no opsonisation at all.
Only opsonised bacteria were internalised rapidly and processed to
terminal phagolysosomes. These data challenge the traditional paradigm
of the AM as the primary innate defence against inhaled pneumococci.
It is more likely that the role of the AM in pneumococcal disease is as a
sentinel phagocyte, producing a rapid pro-inflammatory signal after
ingestion of small numbers of bacteria.
Klebsiella and nosocomial pneumonia
The nasopharyngeal flora of severely ill hospital in-patients changes

within a few days of admission to include Gram-negative bacteria, such

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as Klebsiella pneumoniae and Pseudomonas aeruginosa. The bacteria

may rapidly descend the respiratory tract (particularly in the presence of
an endotracheal tube) causing ciliary dysmotility, epithelial damage, and
extensive inflammation. Lipopolysaccharide (LPS) in the cell walls of
Gram-negative bacteria is markedly pro-inflammatory and directly
induces local TNF-α release from macrophages and neutrophils in the
lung when delivered endotracheally. The resulting extensive inflam-
mation is thought to be partly responsible for the high mortality
associated with these infections.
The role of AM in this aggressive inflammatory infection has been
explored using a mouse model from which AM were depleted using
dichloromethylene diphosphonate (DMDP) liposomes delivered by the
endotracheal route33. AM were required for successful clearance of even
small inocula of K. pneumoniae despite adequate recruitment of neutrophils
in the AM-depleted mice. The absence of AM led to a dramatically higher
mortality in the study mice, which was attributed to the lack of counter-
inflammatory mechanisms mediated by AM. Evidence to support this came
from the excessively high levels of pro-inflammatory cytokines (TNF-α and
MIP-1α) measured in lung and plasma.
Legionella and intracellular pathogens
Certain bacteria such as Legionella pneumophila are adept at subverting

the normal macrophage defences to allow intracellular replication. This
type of interaction is confusing because the macrophage provides both
the niche for the parasite and is also a critical component of the eventual
mechanism to clear the infection34. Persistence in an intracellular site is
potentially advantageous to the bacteria as it is protected from humoral
defence mechanisms.
Legionella do not actively penetrate the AM but are bound to the
complement receptor and subsequently internalised using coiling
phagocytosis. Intracellular bacteria replicate rapidly (3 logs in 2 days) in
ribosome-studded vacuoles which do not acidify normally due to a failure
of phagolysosome fusion. Macrophage death ensues releasing thousands of
new bacteria to repeat the cycle. Antibody and complement responses to
the bacteria develop but appear only to enhance the entry of bacteria into
further macrophages35. Effective humoral responses to L. pneumophila
decrease the subsequent intracellular rate of replication of the bacteria
(presumably due to internalisation via the fcR rather than the CR)36.
Eventual killing of L. pneumophila by macrophages is thought to be
dependent on cytokine-mediated activation (TNF-α and IFN-γ) of alveolar
macrophages. Pretreatment with TNF-α and IFN-γ (or LPS which induces
the former) synergistically increases the resistance of alveolar macrophages

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to experimental infection with L. pneumophila37. Further, addition of IL-

10 increases susceptibility of host AM to L. pneumophila infection38 and
L. pneumophila have been shown to inhibit IL-12 production by the
macrophage (and hence inhibit IFN-γ production)39.
Macrophage defences against Mycobacterium tuberculosis
Mycobacterium tuberculosis enters macrophages via mannose and

complement receptors40, but the bacterium is sufficiently versatile that
selective receptor blockade does not alter the rate of bacterial entry41.
Surfactant protein D reduces mycobacterial entry via the mannose receptor,
but surfactant protein A increases uptake42. Mycobacteria have been shown
to alter lysosome trafficking43, and phagolysosome fusion in particular44, in
order to survive in an intracellular compartment. Macrophage apoptosis of
the host cell, however, is an effective mechanism evolved by the host to
contain the bacteria in dense, non-inflammatory compartments that can
then be phagocytosed more effectively by fresh, activated macrophages. The
bacteria, however, may block host macrophage apoptosis by a TNF-
receptor dependent mechanism45,46.
The mechanisms of effective anti-tuberculous host defence are still being
explored, but the subject has now reached an additional level of complexity
due to the global association of HIV and TB. There is a complex intra-
cellular interaction between HIV and TB. Briefly, Mycobacteria modulate
the replication rate of HIV in macrophages, initially increasing HIV
production but causing inhibition if the macrophage is activated47. This
inhibition is mediated by macrophage chemokine production (RANTES)
and down-regulation of chemokine receptors48.
Finally, as with Legionella, successful outcome in Mycobacteria infection
of the macrophage depends on an optimal cytokine profile resulting in
appropriate macrophage activation. Recent work has confirmed that the
TNF-α and IFN-γ synergy is again crucial, probably by a nitric oxide
dependent mechanism which can be inhibited by IL-10 and enhanced by IL-
12 and IL-1849. It has been demonstrated that IL-1250 and IL-12 receptor51
deficient patients suffer severe, recurrent infections with Mycobacteria. In
other studies, IL-18 (previously called INF-γ inducing factor) production by
PBMC correlated with effective macrophage immunity to Mycobacteria52.
Macrophage defences against fungi

(Candida and Pneumocystis carinii)
Prior to the onset of the HIV pandemic, fungal infections of the lung
were exceedingly rare. HIV infection of AM has been shown to impair

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macrophage function, and HIV-infected patients experience an excess of

fungal infections.
Fungal infections with Candida albicans are commonly characterised
by the colonisation of epithelial surfaces, typically of the oral and genital
mucosa. The fungus remains an extracellular parasite and rarely
breaches the mucosal surface although bacteraemia can occur. Fungal
pneumonia is seen in severely immunocompromised patients.
Normal AM internalise C. albicans rapidly but kill the fungus slowly.
Killing occurs more rapidly if AM are pretreated with IFN-γ, IL-1, LPS or
GM-CSF53. Further, intratracheal immunisation with C. albicans sub-
stantially improved fungal clearance on re-challenge54. From these data, it
is inferred that AM defences are important, inducible and sensitive to the
effect of cellular and humoral responses which are probably locally
regulated by DC presenting antigen at local lymph nodes.
Pneumocystis carinii is an unusual opportunistic pulmonary pathogen
(previously categorised as a protozoon) in that it remains an extracellular
parasite and causes an inflammatory disease at alveolar level in severely
immunocompromised patients. Acute pneumonic illness due to P. carinii is
a frequent AIDS defining event. At the alveolar level, AM are the primary
defence mechanism – the fungus is internalised by normal AM via mannose
receptors55 that are up-regulated in response to acute infection. P. carinii is
killed by an effective AM oxidative burst which can be enhanced by
exogenous GM-CSF. Increased levels of surfactant protein A (SP-A) are
found in PCP patients, but these are unhelpful as SP-A has been shown to
reduce effective macrophage binding of the pathogen56.
HIV infection causes down-regulation of mannose receptors55, and
impairment of the oxidative burst in response to P. carinii28. P. carinii
infection causes an increase in HIV replication in AM.
Failure of macrophage defences

As macrophages are the primary resident phagocyte of the resting human
lung, it is intuitive that any functional impairment leads to infection by
micro-organisms.
Congenital
Patients exhibiting congenital macrophage defects of phagocytosis are rare

because the effects of these syndromes are so severe. Macrophages have
multiple regulatory functions as well as the anti-infective roles that have
been the focus of this paper. Gaucher’s syndrome, for example, in which a
lysosomal disorder causes abnormal accumulation of glucocerebroside in

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macrophages (Gaucher’s cells), consists of hepatosplenomegaly, bone

marrow replacement, skeletal disease, lung infiltration, a hypermetabolic
state and neurological lesions.
Less severe defects are probably under-recognised. IL-12 and IL-12
receptor defects have already been mentioned in patients with increased
susceptibility to intracellular infections50,51. Polymorphisms of the fc receptor
have also been described. Patients with poorly functional receptor
polymorphisms are at increased risk of infections with capsulate organisms,
primarily Strep. pneumoniae57.
Acquired macrophage defects (HIV, drugs, sepsis syndrome)

Acquired macrophage defects are very common and are probably under-
recognised in clinical practice. Pulmonary macrophage defects occur by a
number of different mechanisms including response to infection, mal-
nutrition, cigarette smoking and environmental pollution, and drugs.
Infections
Infections are a major cause of acquired impaired macrophage function.
Chronic infection with the HIV virus has been mentioned, and acute viral
infections also produce a transient decrease in AM function. This may
contribute in part to the excess of bacterial pneumonia seen following viral
infection, particularly during ‘flu epidemics’, but increased adherence of
bacteria to respiratory epithelium is a known significant factor in these
infections58.
Severe bacterial infections are associated with maladaptive cytokine
release with consequent shock and multi-organ failure. Patients with this
syndrome are prone to severe pneumonia. Recent work has shown that the
increased susceptibility to pneumonia may be due to AM inhibition by an
immunomodulatory mechanism. TNF induces IL-10 mediated suppression
of AM function59. Initial attempts to treat the sepsis syndrome with anti-
TNF antibodies produced an increased mortality. Paradoxically, however,
intrapulmonary TNF gene therapy has been shown to improve survival in
an animal model of the sepsis syndrome60 using Ps. aeruginosa. Thus it has
been postulated that an intense inflammatory episode in the lung results in
immediate TNF production followed by relative immunosuppression. As
bacteraemia progresses, TNF levels remain high or rise in the blood just as
IL-10 mediated immunosuppression is taking effect in the lung14.
Other mechanisms are also at play in the macrophage inhibitory effects
of bacterial infection including inhibition of leukotriene metabolism61 and
induction of macrophage apoptosis. Bordetella spp.62 and Strep.
pneumoniae60 have been shown to induce apoptosis in AM in vitro.
Different patterns of apoptosis have been shown to determine patterns of
resolution in pulmonary infection64.

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Malnutrition
Malnutrition in children and adults is well known to be associated with
respiratory tract infections. This is demonstrated most clearly in the
epidemiology of poverty, malnutrition and disease among children in
Africa. Increased rates of pulmonary infection are also seen among patients
receiving parenteral nutrition, alcoholics and patients with selected
nutritional defects. Macrophage defects have been demonstrated in all
these groups.
Cigarette smoking and environmental pollution

Both are known to produce an increase in respiratory infections in children
and adults predominantly due to effects on bronchial innate immunity and
humoral responses65. Macrophage abnormalities have also been demon-
strated in smokers (but not yet correlated with increased susceptibility to
infection) and increased apoptosis induced by diesel exhaust particulates by
a mitochondrial mechanism has recently been described66,67.
Drugs
Drugs cause macrophage defects. Heroin addicts have increased sus-
ceptibility to pulmonary infections for several reasons including mal-
nutrition and social circumstances but morphine has also been shown to
increase AM apoptosis68. The immunosuppressive effect of oral cortico-
steroids and cytotoxic drugs are well known, but inhaled steroid has also
been shown to decrease AM production of TNF-α69.
Therapeutic options
From this discussion it is clear that AM response to pathogens varies
according to the invading pathogen. Macrophages vary between humans
and between compartments within humans. Novel therapeutic strategies to
enhance antimicrobial effectiveness will have to allow for this specificity.
Targeted protein delivery to macrophages has been achieved in the
treatment of Gaucher’s disease. Recombinant glucocerebrosidase was
delivered to macrophages by modification of the enzyme molecule to
enhance binding to the mannose receptor69.
Inhaled antibiotics have been in use for many years, and inhaled
immunomodulatory drugs are fundamental in the control of asthma.
The use of inhaled immunomodulatory treatment in the management of
infection, however, is not yet used due to the complexity of relationships
outlined in the discussion above. In future, however, it is likely that
specific immunomodulation will be of therapeutic benefit, particularly
in the treatment of persistent intracellular infections.
Gene transfer systems for delivering specific therapy to the respiratory
tract have already been developed in the management of cystic fibrosis.

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The temporary effect of these treatments (due to epithelial shedding)

makes them ideal for the management of infective episodes and indeed
a successful animal model of TNF gene therapy for pulmonary infection
has been developed60.
Key points for clinical practice

• Macrophages are a heterogeneous group of cells with roles in antigen
presentation, T cell activation, antibody production and immunomodulation as
well as phagocytosis
• Alveolar macrophages are susceptible to infection themselves, particularly by
HIV and TB
• Macrophage function is altered by infection, environmental exposure to toxins,
inhaled particles and drugs
• Macrophage function is a potential target for novel therapeutic intervention.
Acknowledgements
This work received financial support from the Wellcome Trust of Great
Britain (Career Development Fellowship held by SBG – grant number
063675) and forms part of the Malawi-Liverpool-Wellcome Trust
Programme of Research in Clinical Tropical Medicine.
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Macrophage defences against respiratory

S B Gordon*,† and R C Read†

Pulmonary macrophages with a key role in defence against respiratory infection

Origin and types of respiratory tract macrophages

British Medical Bulletin 2002;61: 45–61  The British Council 2002

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have varied phenotype according to the location, function and state of

Alveolar macrophages (AM) form 95% of the cell burden in broncho-

Dendritic cells (DC) share a common precursor with AM but

46 British Medical Bulletin 2002;61

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DC are extremely efficient antigen-presenting cells but weak phago-

Overview of macrophages in respiratory tract defences

Innate and acquired immunity

Immune responses can be subdivided into innate and acquired systems

British Medical Bulletin 2002;61 47

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Fig. 1 Immunofluorescence of human alveolar macrophages infected with Strep.

48 British Medical Bulletin 2002;61

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Anatomical location and macrophage specialisation

British Medical Bulletin 2002;61 49

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Compartmentalisation of the immune response

Macrophage defences against viruses

Respiratory syncitial virus (RSV) – a battle often won

Macrophages, specifically dendritic cells, play a central role in defence

50 British Medical Bulletin 2002;61

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activation of epitope-specific T cells15. These T-cells migrate back to the

Human immunodeficiency virus (HIV) – a battle often lost

Infection with HIV usually involves macrophage-tropic strains. The virus

British Medical Bulletin 2002;61 51

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with increased susceptibility to M. tuberculosis by a surfactant A dependent

Macrophage defences against bacteria

Strep. pneumoniae is the most common cause of community acquired

Klebsiella and nosocomial pneumonia

The nasopharyngeal flora of severely ill hospital in-patients changes

52 British Medical Bulletin 2002;61

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as Klebsiella pneumoniae and Pseudomonas aeruginosa. The bacteria

Legionella and intracellular pathogens

Certain bacteria such as Legionella pneumophila are adept at subverting

British Medical Bulletin 2002;61 53

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to experimental infection with L. pneumophila37. Further, addition of IL-

Macrophage defences against Mycobacterium tuberculosis

Mycobacterium tuberculosis enters macrophages via mannose and

Macrophage defences against fungi

54 British Medical Bulletin 2002;61

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macrophage function, and HIV-infected patients experience an excess of

Failure of macrophage defences

Patients exhibiting congenital macrophage defects of phagocytosis are rare

British Medical Bulletin 2002;61 55

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macrophages (Gaucher’s cells), consists of hepatosplenomegaly, bone

Acquired macrophage defects (HIV, drugs, sepsis syndrome)

56 British Medical Bulletin 2002;61

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Cigarette smoking and environmental pollution

British Medical Bulletin 2002;61 57