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), H
2
O
2
,
and HOCL, and it has been
well established that oxidants can act jointly with neutrophilic
proteases to increase the degree of tissue damage by inactivating
the participation of antiproteases (through oxidation of the
methionine of -1-antitrypsin, for example) and/or perhaps
by altering the protein structure and thus making molecules
more susceptible to proteolytic attack [2,76].
In the absence of a stimulus, neutrophils have been
J Investig Allergol Clin Immunol 2009; Vol. 19(5): 340-354 2009 Esmon Publicidad
J Monteseirn 345
seen to produce more superoxide in atopic
than in nonatopic individuals [76]. While it
might seem that this is due to alterations in
atopic patients, this is not the case as it was
seen that the difference remained signicant
following the stimulation of neutrophils
with calcium ionophore A23187 and the
chemoattractant fMLP. Similar results have
been seen for fMLP in other studies [77,78].
Neutrophils have also been found to produce
more toxic oxygen radicals in asthmatic
patients compared to controls when stimulated
with PMA [78] or opsonized zymosan [76-78].
The production of O
2
-
has been seen to be
inversely proportional to FEV
1
values [79]
and to bronchial hyperreactivity induced by
methacholine [78] and histamine [77] (in both
cases at the amount required to cause a 20%
drop in FEV
1
) . Furthermore, greater amounts
of O
2
following
neutrophil stimulation with fMLP, and more so in allergic
patients than in healthy controls [76-80]. Dexamethasone and
azelastine have a greater inhibitory effect on O
2
production in
healthy controls than in allergic patients, suggesting a greater
resistance to the effect of these medicines in atopic processes
either because of a greater and more persistent presence of
PAF and LTB4 in allergic patients or because of an intrinsic
alteration in the patients themselves [79,81].
Neutrophils from the BAL uid of asthmatic patients
have been seen to produce greater amounts of toxic oxygen
radicals than those from a reference group of healthy
controls [81]. While platelets inhibited the formation of O
2
in the neutrophils of healthy controls, they did not do so in a
patient with severe asthma and an increased platelet count.
The authors of the study suggested that there might be an
abnormal relationship between platelets and neutrophils in
certain types of asthma.
Our group has observed that the in vitro challenge of
neutrophils from allergic patients with an antigen responsible
for their clinical picture led to an increase in the respiratory
burst of these cells [82]. The increase observed was directly
dependent on the concentration of the antigen and the time
during which it acted. The activation was specic since it did
not take place when an antigen to which the patients were not
sensitized was added or when cells from healthy controls were
used. Following stimulation with the antigen, we detected the
incorporation of the 2 cytoplasmic components of the NADPH
oxidase, p47 and p67, into the cell membrane to form the active
NADPH oxidase. In our model, stimulation of the antigen-
specic respiratory burst in allergic patients was inhibited
when antihistamines (loratadine, terfenadine, cetirizine
and carebastine), sodium nedocromil, and corticosteroids
(budesonide and dexamethasone) were added [unpublished
observations]. In another study, we saw a greater production
of respiratory burst in patients with asthma than in healthy
controls following stimulation with anti-IgE antibodies [83];
the asthmatic patients receiving immunotherapy, in contrast,
showed a reduction in respiratory burst to levels comparable
to those of healthy subjects [83].
Neutrophil factors involved in the initiation and maintenance
of late allergic reactions are released at 18 hours after the
challenge of these cells.
Eosinophil Cationic Protein
ECP is a powerful cytotoxic molecule with a capacity
to kill diverse cells in mammals and a wide variety of other
organisms, including parasites, bacteria, and viruses. This
protein plays an important role in resistance to parasites and
in allergic reactions. ECP has traditionally been reported as
being specic to eosinophils, with levels correlating with
eosinophil activity in allergic rhinitis, asthma, conjunctivitis,
and atopic dermatitis [84]. Recent studies, however, have also
demonstrated the presence of ECP in human neutrophils [85],
and others have found ECP levels to be more closely related
to the presence/activation of neutrophils than to that of
eosinophils in various allergic processes [86]. Our group, for
example, demonstrated that ECP was found in and could be
released and synthesized from the neutrophils of asthmatic
patients [85]. Firstly, ECP can be measured by enzyme-
linked immunoabsorbent assay and immunoblotting in the
supernatants of stimulated neutrophils. Secondly, an increase in
intracellular ECP can be detected by means of ow cytometry
and uorescent microscopy, and thirdly, when neutrophils are
stimulated, ECP mRNA levels can be quantied using real-
Neutrophils and asthma
J Investig Allergol Clin Immunol 2009; Vol. 19(5): 340-354 2009 Esmon Publicidad
346
time polymerase chain reaction. As with other
mediators, these results are very specic, and
only take place with allergens to which patients
are sensitized and not in nonsensitized patients
or healthy subjects. There are several differences
between the release of ECP by eosinophils and
that by neutrophils. In the rst case, it takes
place very quickly, in 10 to 30 minutes, whereas
in the second case it requires between 3 and
18 hours. Many soluble stimuli, such as IL-5,
GM-CSF, and PAF, practically do not release
mediators from eosinophils by themselves,
but they do in neutrophils. Neutrophils, unlike
eosinophils, release ECP if stimulated with
allergen or anti-IgE antibodies [85]. ECP
participates in the pathophysiology of asthma
through its cytotoxic capacity, which stimulates
the release of histamine from basophils and
lactoferrin, and causes an increase in bronchial
mucus [84].
Interleukin 8
IL-8 is a powerful chemoattractant and
activator of neutrophils. In the lungs, it seems to
be the most potent chemoattractant for these cells.
Although IL-8 can be produced by several cell
types, it can also be synthesized by neutrophils
in response to various inammatory mediators.
The production of IL-8 by neutrophils, thus,
can contribute to an additional recruitment of
neutrophils and, importantly, increase or prolong the
activation of neutrophils in an autocrine form.
Increased IL-8 levels have been observed in
induced sputum, BAL uid, and tracheal suction
specimens from patients with asthma compared
to controls [87], and a greater release of both nasal
and bronchial IL-8 following a specic antigen
challenge has also been reported [87]. Asthma
exacerbations following the withdrawal of inhaled
corticosteroids have been associated with a
signicant increase in sputum IL-8 and neutrophil
inux 2 weeks prior to the exacerbation [88]. This
could have important clinical implications because
there appears to be a window during which it
might be possible to adjust asthma treatment [88].
In addition to demonstrating that IL-8 is produced
by neutrophils in atopic patients, our group has
also shown that IL-8 synthesis is stimulated in
association with an increase in mRNA expression.
The process is based on a mechanism dependent
Figure 3. In ast hma, t he pat hophysi ol ogi cal consequences of t he i mmunogl obul i n Edependent
act i vat i on of neut r ophi l s ar e numer ous. ROS i ndi cat es r eact i ve oxygen speci es; M PO,
myel operoxi dase; TXA2, t hromboxane A2; IL, i nt erl euki n; ECP, eosi nophi l cat i oni c prot ei n.
Figure 4. Di f f erent agent s can modul at e i mmunogl obul i n (Ig) E-dependent neut rophi l act i vat i on.
The most i mport ant modul at or i s speci c al l ergen i mmunot herapy. ECP i ndi cat es eosi nophi l
cat i oni c prot ei n; ROS, react i ve oxygen speci es; MPO, myel operoxi dase; IL, i nt erl euki n.
on the Ca2
+
-calmodulin-calcineurin axis and the stimulation
of the nuclear factor B [89-91]. Antihistamines (loratadine
>terfenadine>cetirizine), corticosteroids (budesonide and
dexamethasone), and immunotherapy are able to inhibit the
production and release of IL-8 by the neutrophils of allergic
patients following IgE-dependent stimuli.
Although our group was initially unable to detect nuclear
factor of activated T cell (NFAT) activity in neutrophils [91],
we have since veried the presence of mRNA for 4 of the 5
isoforms of NFAT in these cells: NFAT1 (NFATp), NFAT2
(NFATc), NFAT4, and NFAT5. Of these, only NFAT2
translocates to the nucleus when cells are stimulated with
allergen or anti-IgE antibodies. This response is stimulus
specic since it only occurred when allergens to which the
patients were sensitized were used, indicating that this nuclear
factor is activated by an IgE-dependent mechanism [92].
J Investig Allergol Clin Immunol 2009; Vol. 19(5): 340-354 2009 Esmon Publicidad
J Monteseirn 347
Evidence exists that NFAT2 plays an important role in the
induction of T
H
2 cytokines. In 1 study, a mutant NFAT2-
decient mouse was found to be unable to secrete IL-4 [93].
Our ndings are consistent with these concepts, since an
IgE-dependent mechanism would stimulate the production of
T
H
2 cytokines such as IL-4, which have also been found to
be present in and to be released by neutrophils [94]. It would
also contribute to a perpetuation of the allergic process from
the originating regulation of the neutrophils.
Neutrophils can be activated through the 3 IgE receptors, but
primarily through galectin-3 andespeciallyFcRI. According
to studies by our group, all these IgE-dependent neutrophil
effects can be modulated by antihistamines, corticosteroids,
and immunotherapy, the last of which has the greatest effect
on the IgE-dependent activation of neutrophils.
The Neutrophil as a Regulatory Cell in
Asthma
Atopy is a pathologic process in which, following the
recognition of allergens by antigen-presenting cells (APCs),
an immunological response develops under the inuence of T
cells that induces the synthesis of IgE by B cells, whichwhen
bound by their Fc portions to the different cell receptors, and
after recognition of the antigen responsible for the clinical
diseaseinduce the release of mediators and the accumulation
of inammatory cells at the site of inammation. Various
inammatory cells (macrophages, lymphocytes, mast cells,
basophils, eosinophils, neutrophils, and platelets) have been
found to be involved in the allergic reaction, but the roles
played by each of them have not been fully elucidated.
APCs play a key role in the immunological response as
they present antigen to T cells, which is necessary to eventually
achieve a complete response. In allergic processes, such as asthma,
the processing of an allergen and its presentation to the T cell
receptor (TCR) by the HLA-II complex (signal 1) are needed.
The complete development of the process requires costimulation
(signal 2) mediated by the union of CD28 in the T cells with
CD80 or CD86 in the APCs. This interaction allows CD28 to
combine with the TCR, leading to an additional activation of the
complex. Other accessory molecules are also required to complete
the activation of T cells such as leukocyte function-associated
antigen-1 (LFA-1) in the T cells, and its main receptor, ICAM-1
in the APCs. Another pair of adhesion receptors is formed by CD2
in the T cells and CD58 (LFA-3) in the APCs. Various cytokines,
such as TGF- and IL-10 can regulate this activation [95,96].
Immature dendritic cells (DCs) are distributed throughout
the different tissues of the body, where they come into contact
with different stimuli (necrotic cells, microorganisms, etc.)
and are subsequently presented to T cells. This process can
last from minutes to hours, depending on the tissue where the
reaction takes place.
As DCs mature, they change their phenotype and their
functional activity is inuenced by varying factors such as the
nature of antigens (microorganisms, apoptotic/necrotic cells),
the microenvironment, and endogenous signals, all factors that
can lead to antigen-specic T-cell activation or the induction
of immunological tolerance [97-106].
Neutrophils do not return to circulation but are either
eliminated by secreting mucosa or die in the tissues within
1 to 2 days. One means by which neutrophils are destroyed
is apoptosis, or genetically programmed cell suicide. After
apoptosis, they are eliminated by both professional phagocytes
(macrophages) and non-professional phagocytes (eg
broblasts). Neutrophil life span can be prolonged by different
signals in inamed tissues via the suppression of apoptosis.
Obviously, this is not only an effect of extrinsic mediators, but
also an action of the intrinsic neutrophil resources of autocrine/
paracrine regulation [107]. The mitochondrial pathway of
apoptosis is dependent on the B-cell CLL/lymphoma 2 (BCL-2)
protein family (whose members include the BCL-2 associated
x protein [BAX]) for the efcient release of pro-apoptotic
factors such as the second mitochondria-derived activator of
caspase (SMAC) from the mitochondrial intermembrane space.
These factors induce caspase activation, which is necessary to
elicit the phenotypes associated with apoptosis. The BCL-2
family also contains antiapoptotic proteins such as myeloid cell
leukemia-1 (MCL-1). In patients with atopic asthma, human
IgE delays neutrophil apoptosis but this effect is not dependent
on either FcRI crosslinking or the autocrine release of soluble
mediators. It is, however, associated with MCL-1 activation
and BAX and SMAC retention, which induces a reduction in
caspase-3 activity. IgE-dependent delayed neutrophil apoptosis
in allergic patients may therefore contribute to persistent
neutrophilic inammation in atopic asthma [108].
The fact that neutrophils play an immediate role in immune
defense requires their early arrival at the inammation site,
making them ideal candidates for controlling the recruitment
of other cell types to this site. Activated neutrophils produce
several chemokines, including IL-8, growth-related oncogene-
(GRO-), macrophage inammatory protein 1- (MIP-1),
and MIP-1 [109]. IL-8 and GRO- are chemoattractive for
neutrophils and therefore form a positive feedback loop that
induces the accumulation of large numbers of neutrophils.
MIP- and MIP- attract immature DCs in addition to T cells,
monocytes, and macrophages [110], while -defensins, which
are released during neutrophil degranulation, have been found
to chemoattract both T cells and immature DCs [111]. Immature
DCs also produce IL-8 soon after stimulation, thereby attracting
neutrophils and contributing to their colocalization [112]. As
a result, crosstalk between neutrophils and DCs in different
pathogenic challenge situations is enabled as the cells are
located in the same place at the same time. Neutrophils play a
direct role in adaptive immunity via various mechanisms. They
recruit immune cells such as T cells and DCs to the inammation
site, instruct these cells directly, and induce adaptive immune
responses. During inammation, neutrophils are able to travel
from the inammation site to the nearest lymph node [113],
where they undergo apoptosis and are taken up by DCs. As a
consequence, DCs can present neutrophil-derived antigen to
T cells. Neutrophils have also been found to acquire antigen-
presenting functions, thereby enabling them to directly activate
T cells [114]. Finally, they can directly transfer antigens to DCs,
which subsequently activate T cells [115].
Like other cells such as lymphocytes, macrophages, and
natural killer cells, neutrophils are able to synthesize and
release a great variety of cytokines that play a key role in the
Neutrophils and asthma
J Investig Allergol Clin Immunol 2009; Vol. 19(5): 340-354 2009 Esmon Publicidad
348
development of the immune response. Examples include IL-1,
IL-3, IL-6, IL-8, TNF-,IL-12, IFN-, GM-CSF, MIP, and
TGF-.
The surface-expressed lactoferrin released from neutrophils
after contact with autologous CD4
+
T cells has been seen
to suppress T
H
1 cytokine but with a tendency to enhance
T
H
2 cytokine production [116]. Puellmann et al [117] have
demonstrated the presence of TCR in neutrophils. Activation
of the neutrophil immunoreceptor by known TCR agonists
increases IL-8 secretion and inhibits neutrophil apoptosis.
These results suggest that the activation of TCR in neutrophils
and the subsequent release of IL-8 may contribute to neutrophil
inammation in patients with atopic asthma.
The constitutive expression of MHC class II antigens is
restricted to professional APCs, such as DCs, B cells, and
cells of the monocyte/macrophage lineage. Such antigens
are not expressed in the neutrophils of healthy individuals
but their induction has been described in both mature and
precursor neutrophils [118] in response to interferon (IFN)-
GM-CSF, and/or IL-3 [119,120]. The expression of MHC class
II on the surface of neutrophils has been found to be donor
dependent [121] and has also been reported in vivo in Wegeners
granulomatosis [122], rheumatoid arthritis [123], tuberculosis
pleural effusions [124], and following the administration of
GM-CSF, granulocyte CSF, and IFN- [125-127].
The only known function of MHC class II antigen is
the presentation of antigens to cells. Costimulatory signals
are required, however, for the full activation of T cells;
such signals are delivered via the interaction between APC
receptors and T-cell counterreceptors. Multiple pairs of
costimulatory molecules, ICAM-1 (CD54), and LFA-3 (CD58)
are constitutively expressed on neutrophils [128]. Other
molecules, such as CD80 and CD86, which are both ligands
for CD28 in T cells, are not expressed on nave neutrophils,
but are synthesized de novo in response to IFN-, GM-CSF,
or a combination of both [118,129].
There is experimental evidence that neutrophils themselves
act as APCs. When neutrophils are cultured with staphylococcus
enterotoxinalso called superantigenand T cells, the latter
proliferate. The use of staphylococcus enterotoxinin in this type
of experiment has several advantages: a) the antigen does not
need to be processed, b) there is only a relative dependency
on the haplotype DR, and c) antigen-specic T cells are not
needed because stimulation by heterologous cells is possible.
As most T cells respond to superantigen, there is a signicant
proliferation of these cells, making these experiments easy to
perform and reproduce. However, presentation of superantigen
is very different from the more complex presentation of peptide
antigens (which is what occurs in the development of allergic
responses). In contrast to the presentation of superantigens,
that of peptides to T cells requires processing of the antigenic
protein by the APCs, followed by the union of the processed
peptide molecules to HLA II and the transfer of the HLA II-
peptide complex to the cell surface. Because the clefts formed
by the 2 chains of HLA to which the peptides are joined vary
with the haplotype DR, there is a certain selectivity with
respect to the peptides that may be presented/displayed. It
has also been found, using tetanic toxin, that neutrophils can
act as APCs [129].
Our group has shown that neutrophils from allergic patients
modulate the expression of their cell-surface HLA-DR molecules
after cytokine activation in different amounts to neutrophils from
healthy controls do [unpublished observations]. We found that
the expression of MHC II on neutrophils was signicantly
higher in asthmatic patients not receiving immunotherapy than
in a healthy group. In agreement with our results, other authors
have shown that allergic patients have a greater expression of
HLA-DR in different cells such as basophils [130], B cells [131],
and in cellular inltrates at the sites of allergen-induced late-
phase cutaneous reactions [132]. The mechanisms leading to
the described ndings are complex. Upregulation of HLA-DR
in allergic patients compared to healthy subjects can be partially
explained by changes to the cytokine microenvironment in
neutrophils from atopic patients. Because neutrophils are able to
produce and store IL-4, an autocrine stimulation is possible. IL-4
is also responsible for MHC II expression in mast cells [133]. The
same effect (IL-4-induced MHC II expression) can be assumed
for neutrophils. We have previously shown that allergens have
direct effects on neutrophils in vitro [unpublished observations]
but these effects in vivo may also contribute to the observed
modulations in HLA-DR surface expression.
Immunotherapy has been seen to negatively modulate
IgE-dependent upmodulation in HLA-DR surface expression
in neutrophils from atopic patients who had received allergen
immunotherapy [unpublished observations]. Immunotherapy
produces a downmodulation of HLA-DR molecules on the
surface of other cells, such as B cells [131,134], basophils [130],
and T cells [135]. HLA-II is the key molecule for APCs. The fact
that immunotherapy in asthmatic patients has been associated
with a reduction in the percentage of neutrophils expressing the
HLA-DR
+
marker suggests that immunotherapy acts directly on
these cells to reverse their APC status.
Functions based on IgE-mediated mechanisms, such as the
production of superoxide and LTC4, or the release of EDN and
ECP, have not been observed in human eosinophils, although
these show a vigorous response to IgG3- and IgG1-mediated
stimuli through the FcRII receptor [86,136-142]. These
ndings have led some authors to conclude that factors other
than IgE and its receptors must act as inducers of the activation/
release of eosinophils in allergic diseases [136]. It is possible
that neutrophils might be responsible for the activation/release
of eosinophils in IgE-mediated atopic processes [143].
The mediators secreted by neutrophils have the following
effects on eosinophils:
They attract eosinophils to the focus of inammation
causing their chemotaxis, either directly [144], or through IL-8,
which is a powerful chemoattractant for these cells [145].
Elastase released by neutrophils causes degranulation of
eosinophils, releasing considerable amounts of ECP, depending
on the dose of elastase [146].
Neutrophilic lactoferrin, in quantities similar to those
found in airway uid [143], has several effects on eosinophils:
degranulation with the release of EDN, superoxide production,
and the synthesis of leukotrienes with the subsequent secretion
of LTC4 [148].
In addition to its normal functions, ECP can
release lactoferrin from the serous glands of the airway
mucosa [149].
J Investig Allergol Clin Immunol 2009; Vol. 19(5): 340-354 2009 Esmon Publicidad
J Monteseirn 349
More recently it has been shown that neutrophils, in
addition to IL-8, MMP-9, LTB4, PAF, and TNF-, induce
eosinophil trans-basement membrane migration [150].
Murine neutrophils produce IL-17 [151] and this
cytokine mediates eosinophil activation via differential
intracellular signaling cascades in allergic inammation [152].
IL-23 and IL-6 promote the survival and differentiation of
IL-17producing cells. Two families of lipid agonists control
the magnitude and duration of inammation: protectins and
resolvins. Resolvin E1 has been seen to decrease the production
of the proinammatory cytokines Il-23, IL-6, and IL-17, and
to increase that of the counter-regulatory mediators IFN-
and lipoxin A4 to promote the resolution of allergic airway
inammation [153].
Neutrophil proteases (elastase, cathepsin G, and proteinase-3)
may enhance airway inflammation in asthma through the
activation of eosinophils to produce superoxide and neutrophilic
cytokines and chemokines. The mechanism may underlie part of
the pathogenesis of severe asthma, and effective inhibition of these
proteases could be a future therapeutic target [154].
In conclusion, although eosinophilic airway inammation
is recognized as an important feature of certain forms of
chronic, stable asthma, evidence also supports an important
role for neutrophils in this disease. Because neutrophils are
the rst cells recruited to the site of an allergic reaction, they
may inuence clinical presentation and play a role in the
development of severe chronic asthma and the onset of sudden
severe attacks. Neutrophils are removed by apoptosis during
the resolution of the allergic response.
Funding Sources
This work was supported by grants from the Junta
de Andalucia (Ayudas Grupos de Investigacin) and the
Asociacin Sanitaria Virgen Macarena and Fundacin Alergol
in Sevilla, Spain. J.M. forms part of the research intensication
program under the Spanish National Health System.
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Javier Monteseirn
Asuncin 27, 3 Izda
41011 Sevilla
Spain
E-mail: fmonteseirinm@meditex.es
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