Eotaxin/CCL11 is involved in acute, but not chronic, allergic
airway responses to Aspergillus fumigatus
Jane M.
Schuh,
Kate
Blease,
Steven L.
Kunkel, and
Cory M.
Hogaboam
Department of Pathology, University of Michigan Medical
School, Ann Arbor, Michigan 48109
 |
ABSTRACT |
Eotaxin/CCL11 is a major
chemoattractant for eosinophils and Th2 cells. As such, it represents
an attractive target in the treatment of allergic disease. The present
study addresses the role of eotaxin/CCL11 during acute and chronic
allergic airway responses to the fungus Aspergillus
fumigatus. Mice lacking the eotaxin gene (Eo
/
) and wild-type
mice (Eo+/+) were sensitized to A. fumigatus and received
either an intratracheal challenge with soluble A. fumigatus
antigens (acute model) or an intratracheal challenge with live A. fumigatus spores or conidia (chronic model). Airway
hyperresponsiveness and eosinophil, but not T cell, recruitment were
significantly decreased at 24 h after the soluble allergen in
A. fumigatus-sensitized Eo
/
mice compared with similarly sensitized Eo+/+ mice. In contrast, the development of chronic allergic
airway disease due to A. fumigatus conidia was not altered by the lack of eotaxin. Together, these data suggest that eotaxin initiates allergic airway disease due to A. fumigatus, but
this chemokine did not appear to contribute to the maintenance of
A. fumigatus-induced allergic airway disease.
eosinophil; allergy; airway hyperreactivity
 |
INTRODUCTION |
SINCE ITS DISCOVERY AND
CLONING in a number of species (21, 36, 38), the
CC chemokine eotaxin/CCL11 has received considerable research
attention in the context of allergy and asthma (37). Although it is constitutively expressed in the lung, eotaxin/CCL11 levels are markedly increased in bronchoalveolar lavage (26, 29), sputum (46), and the airway wall (44,
48, 49) during asthmatic responses. Eotaxin/CCL11 appears to
play a fundamental role in the development of allergic responses due,
in large part, to its effects on the recruitment (10, 17, 39,
40) and activation of eosinophils (12, 35) and Th2
cells (30). Eotaxin/CCL11 appears to mediate this effect
through the CC chemokine receptor-3 (11, 15), and a
growing number of reports highlight the major therapeutic potential in
targeting this chemokine receptor during the development of allergic
airway inflammation (2).
Allergic responses to Aspergillus fumigatus are
characterized by many features associated with asthma, including
elevated IgE, enhanced Th2 cytokine levels, eosinophilia, bronchial
hyperreactivity, and airway remodeling (22, 25). The
eosinophil is a primary cellular culprit in the allergic pulmonary
disease associated with this fungus (27), but few studies
have addressed which factors control eosinophil recruitment into the
airways during the course of this disease. The advent of murine models
of A. fumigatus-induced pulmonary disease have facilitated
study in this regard, and it has become apparent that chemokines are
intricately involved in allergic airway disease due to A. fumigatus. For example, it has been shown that the introduction of
soluble A. fumigatus antigens into the airways of mice
previously sensitized to this fungus initiates an eosinophil-dominated
peribronchial inflammation that persists for up to 48 h after the
challenge and is dependent on the CC chemokine C10/CCL6
(20). More recently, we have begun to examine the
impact of intratracheally introduced A. fumigatus spores (or conidia) on the persistence of allergic airway disease. It
has been shown that CC chemokines that bind CCR1 (7) and CCR2 (6) have important roles in regulating the severity
and features of this chronic fungal asthma model. Thus the purpose of
the present study was to examine the role of eotaxin/CCL11 in the
initiation and maintenance of A. fumigatus-induced asthmatic disease in mice.
 |
MATERIALS AND METHODS |
Murine models of acute and chronic fungal asthma.
Specific pathogen-free (SPF) female eotaxin/CCL11 wild-type (Eo+/+) and
eotaxin/CCL11 knockout (Eo
/
) mice were kindly provided by Dr.
Rodrigo Bravo (Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, NJ). The generation of Eo
/
mice was previously described
in detail, and these mice do not exhibit phenotypic abnormalities
(47). Both groups of mice were bred and maintained under
SPF conditions in the University Laboratory Animal Medicine (ULAM)
facility at the University of Michigan Medical School before and during
experiments. Sensitization of mice to soluble A. fumigatus antigens was achieved using a previously described procedure (32, 33). Briefly, all mice received a total of 10 µg of A. fumigatus crude antigen (Greer Laboratories, Lenoir, NC) dissolved
in 0.2 ml of incomplete Freund's adjuvant (Sigma Chemical, St. Louis, MO). Half of this preparation was then deposited in the peritoneal cavity, and the remainder was delivered subcutaneously. Two weeks later, mice received a total of 20 µg of A. fumigatus
antigens dissolved in normal saline via the intranasal route. To
initiate the acute fungal asthma model (20), mice received
20 µg of A. fumigatus antigen dissolved in normal saline
via the intratracheal route 4 days after one intranasal challenge. To
initiate the chronic fungal asthma model, A. fumigatus-sensitized Eo
/
and Eo+/+ mice received 5.0 × 106 A. fumigatus conidia suspended in 30 µl of
0.1% Tween 80 via the intratracheal route 7 days after the third
intranasal challenge (19). Mouse lung responsiveness to
intravenous methacholine administration and a number of additional
parameters of allergic airway inflammation were examined at various
times after the A. fumigatus intratracheal challenge in both
models. Prior approval for mouse usage in these studies was obtained
from the ULAM facility at the University of Michigan Medical School.
Measurement of bronchial hyperresponsiveness and lung harvest.
Bronchial hyperresponsiveness in A. fumigatus-sensitized
Eo+/+ and Eo
/
mice was measured in a Buxco plethysmograph (Buxco, Troy, NY) as previously described (19). Pentobarbital
sodium (Butler, Columbus, OH; 0.04 mg/g of mouse body wt) was used to anesthetize each mouse before its intubation for ventilation with a
Harvard pump ventilator (Harvard Apparatus, Reno, NV). After a baseline
period in the Buxco mouse chamber, each mouse received 125 µg/kg of
methacholine by tail vein injection, and airway responsiveness to this
bronchoconstrictor was again calculated online. This dose of
methacholine was selected to examine airway hyperresponsiveness in
allergic mice because it failed to elicit a response in nonsensitized mice and consistently gave peak changes in airway resistance in A. fumigatus-sensitized mice. At the conclusion of the
assessment of airway responsiveness, a bronchoalveolar lavage (BAL) was
performed with 1 ml of normal saline. Approximately 500 µl of blood
was then removed from each mouse and transferred to a microcentrifuge tube. Sera were obtained after the sample was centrifuged for 5 min.
Whole lungs were finally dissected from each mouse and snap-frozen in
liquid N2 or prepared for histological analysis.
Morphometric analysis of eosinophil and lymphocyte accumulation
in BAL samples.
Neutrophils, eosinophils, lymphocytes, and macrophages were enumerated
in BAL samples cytospun (Shandon Scientific, Runcorn, UK) onto coded
microscope slides. Each slide was stained with a Wright-Giemsa
differential stain, and the average number of each cell type was
determined after counting a total of 300 cells in 10-20
high-powered fields (×1,000) per slide. A total of 1 × 105 BAL cells were cytospun onto each slide to compensate
for differences in cell retrieval.
Whole lung histological analysis.
Whole lungs from Eo
/
and Eo+/+ mice were fully inflated with 10%
formalin, dissected, and placed in fresh formalin for 24 h.
Routine histological techniques were used to paraffin embed the entire
lung, and 5-µm sections of whole lung were stained with hematoxylin
and eosin. Inflammatory infiltrates and structural alterations were
examined around small airways and adjacent blood vessels using light
microscopy at a magnification of ×200.
ELISA analysis.
Murine eotaxin/CCL11, interleukin (IL)-10, monocyte chemoattractant
protein-1 (MCP-1)/CCL2, interferon-
(IFN-
), IL-13, and C10/CCL6
chemokine were measured in 50-µl samples from whole lung homogenates
(whole lung samples were initially homogenized in 1 ml of saline
containing protease inhibitors) using a standardized sandwich ELISA
technique previously described in detail (13). Each ELISA
was screened to ensure antibody specificity and recombinant murine
cytokines, and chemokines were used to generate the standard curves
from which the concentrations present in the samples were derived. The
limit of ELISA detection for each cytokine was consistently above 50 pg/ml. The cytokine and chemokine levels in each sample were normalized
to total protein levels measured using the Bradford assay (Bio-Rad,
Hercules, CA).
Statistical analysis.
All results are expressed as means ± SE. Two separate experiments
were performed. A Student's t-test was used to reveal
statistical differences between the Eo
/
and Eo+/+ groups in both
fungal asthma models. P < 0.05 was considered
statistically significant.
 |
RESULTS |
Role of eotaxin in an acute model of A. fumigatus-induced allergic
airway disease.
A number of studies have addressed the effects of soluble
Aspergillus antigens on the allergic inflammatory response
within the murine lung (23, 24), and airway eosinophilia
is a prominent feature of this response (20). In the
present study, peak changes in whole lung and BAL levels of
eotaxin/CCL11 were observed at 24 h after the soluble
A. fumigatus antigen challenge (Fig.
1) in Eo+/+ mice. Although the
increases in eotaxin/CCL1 levels in whole lung samples were significant
at 3 and 24 h after the allergen challenge, these increases were
less than a twofold increase above levels measured before the allergen
challenge. No significant increases in BAL levels of eotaxin/CCL11 were
noted at any time after the conidia challenge, rather, BAL levels of
this chemokine were significantly lower at 48 and 72 h after the
allergen challenge (compared with BAL levels before the allergen
challenge; Fig. 1). Determination of methacholine-induced airway
hyperresponsiveness at 24 and 48 h after the soluble allergen
challenge revealed that methacholine-induced airway resistance in
Eo
/
mice was lower at both time points compared with Eo+/+ mice,
with a significant difference detected at 24 h after the allergen
challenge (Fig. 2). Morphometric analysis
of airway-associated eosinophilia revealed that significantly fewer
eosinophils were present in Eo
/
mice at both times after the
A. fumigatus challenge compared with the wild-type control
group (Fig. 3A). In contrast,
lymphocyte numbers (primarily T cells) were higher in the airways of
Eo
/
mice at 24 and 48 h after the soluble allergen challenge,
and this increase reached statistical significance at 48 h after
the allergen challenge (Fig. 3B). One explanation for the
increase in the numbers of T lymphocytes in the airways of Eo
/
mice
may be related to the significant elevations in C10/CCL6 chemokine, a
potent T cell chemoattractant (45), that were observed in
the BAL of these mice at 48 h after the allergen challenge (Fig.
4). Histological examination of whole
lung specimens from Eo
/
and Eo+/+ mice (Fig.
5) revealed that eosinophil recruitment
to the airways was clearly impaired in Eo
/
mice at 24 h (Fig.
5D) and 48 h (Fig. 5F) compared with Eo+/+
mice (Fig. 5, C and E) at the same times. Together, it was clear that the recruitment of eosinophils in the
context of acute fungus-induced allergic airway disease was markedly
impaired, but this impairment did not fully inhibit the development of
acute fungal asthma.

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Fig. 1.
Whole lung and bronchoalveolar lavage BAL eotaxin/CCL11
levels in Aspergillus fumigatus-sensitized wild-type (Eo+/+)
mice at various times after soluble A. fumigatus (Asp)
allergen challenge. Eotaxin/CCL11 levels were measured using specific
ELISAs as described in MATERIALS AND METHODS. Data are
expressed as means ± SE; n = 3 mice/group.
* P 0.05, compared with levels measured before
(t = 0) the allergen challenge.
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Fig. 2.
Airway hyperresponsiveness at 24 and 48 h after a
soluble A. fumigatus allergen challenge in A. fumigatus-sensitized Eo+/+ mice and Eo / (lacking the eotaxin
gene) mice. The baseline airway resistance in all groups was similar
before the methacholine provocation, and these values (units = cmH2O · ml 1 · s 1)
were as follows: Eo+/+ at 24 h, 1.5 ± 0.11; Eo+/+ at 48 h, 1.3 ± 0.5; Eo / at 24 h, 1.5 ± 0.14; Eo / at
48 h, 1.5 ± 0.5. Peak increases in airway resistance after
the intravenous injection of 125 µg/ml of methacholine are shown.
Values are expressed as means ± SE; n = 3 mice/group. *** P 0.001 compared with airway
hyperresponsiveness measured in Eo+/+ mice at the same time after the
soluble A. fumigatus allergen challenge.
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Fig. 3.
Temporal changes in eosinophil (A) and T
lymphocyte (B) counts in BAL samples before and at 24 and
48 h after a soluble A. fumigatus allergen challenge in
A. fumigatus-sensitized Eo+/+ and Eo / groups. BAL cells
were dispersed onto microscope slides and were differentially stained
with Wright-Giemsa stain. A minimum of 15 high-powered fields (HPF) or
300 cells was examined in each cytospin. A total of 1 × 105 BAL cells were cytospun onto each slide to compensate
for differences in cell retrieval from each mouse.
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Fig. 4.
BAL levels of C10/CCL6 before (indicated by dashed line)
and at 24 and 48 h after an A. fumigatus allergen
challenge in A. fumigatus-sensitized Eo+/+ and Eo / mice.
Immunoreactive C10/CCL6 levels were determined using specific ELISAs as
described in MATERIALS AND METHODS. Values are expressed as
means ± SE; n = 3 mice/group. P = 0.006 compared with C10/CCL6 levels measured in the Eo+/+ control group
at the same day after the soluble A. fumigatus allergen
challenge.
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Fig. 5.
Representative photomicrographs of hematoxylin and eosin-stained
whole lung sections before and at 24 and 48 h after a soluble
A. fumigatus allergen challenge in A. fumigatus-sensitized Eo+/+ and Eo / groups. Little
peribronchial inflammation was observed in Eo+/+ (A) and
Eo / (B) mice before the allergen challenge. At 24 h
after the allergen challenge, a marked peribronchial accumulation of
eosinophils and mononuclear cells was observed (C). In
contrast, little peribronchial inflammation was observed in Eo /
mice at this time (D). At 48 h after allergen, the
peribronchial inflammation was very pronounced in Eo+/+ mice
(E), whereas little peribronchial inflammation was apparent
in Eo / mice at this time after allergen (F). Instead,
there appeared to be pronounced perivascular accumulation of
eosinophils and mononuclear cells. Original magnification was ×200 for
each photomicrograph.
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Role of eotaxin in a chronic model of A. fumigatus-induced allergic
airway disease.
We have recently described a model of Aspergillus-induced
airway disease or chronic fungal asthma that persists for several weeks
after the intratracheal introduction of A. fumigatus conidia into A. fumigatus-sensitized mice (19). We have
also observed that many features of this disease, including
peribronchial inflammation, hyperreactivity, and remodeling, are
dependent on the action of various chemokines, including MCP-1/CCL2,
major intrinsic protein (MIP)-1
/CCL3, regulated upon activation,
normal T cell expressed, and, presumably, secreted (RANTES)/CCL5, and
macrophage-derived chemokine/CCL22 (5-7).
Eotaxin/CCL11 was measured by specific ELISA in whole lung and BAL
samples from Eo+/+ mice before and at 3, 7, and 30 days after a conidia
challenge (Fig. 6). In contrast to
eotaxin/CCL11 levels in the acute fungal asthma model, no significant changes in eotaxin/CCL11 were observed at any time after the conidia challenge compared with levels before the conidia challenge.
Measurement of airway hyperresponsiveness induced by exogenous
methacholine challenge revealed similar increases in airway resistance
at all times after the conidia challenge (Fig.
7). Histological examination at day
30 after conidia confirmed that eotaxin did not mediate the
pulmonary disease associated with chronic fungal asthma. No differences
in the degree of peribronchial inflammation or airway remodeling were
observed between the two groups at this time (not shown). Differential
counts of leukocytes in the BAL of Eo
/
and Eo+/+ mice at the
day 30 time point revealed that macrophages were present in
significantly higher numbers in Eo
/
mice compared with Eo+/+ mice,
but all other leukocyte subtypes were similar in both groups (Fig.
8). Some notable differences were
observed in whole lung cytokine and chemokine levels in both groups of mice at day 30 after the conidia challenge (Fig.
9A). Whole lung IL-10 and
MCP-1/CCL2 levels were significantly lower, whereas IFN-
levels were
fourfold lower in Eo
/
mice than levels of the same cytokines and
chemokines measured in whole lung samples from Eo+/+ mice (Fig.
9B). However, prominent levels of IL-13 and C10/CCL6 were
measured in whole lung samples from both groups at this time. Both
IL-13 and C10/CCL6 have significant roles in the maintenance of chronic
fungal asthma (3, 4).

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Fig. 6.
Whole lung and BAL eotaxin/CCL11 levels in A. fumigatus-sensitized Eo+/+ mice at various times after A. fumigatus conidia challenge. Eotaxin/CCL11 levels were measured
using specific ELISAs as described in MATERIALS AND
METHODS. Data are expressed as means ± SE;
n = 5 mice/group.
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Fig. 7.
Airway hyperresponsiveness at days 3, 7, and
30 after an A. fumigatus conidia challenge in
A. fumigatus-sensitized Eo+/+ and Eo / mice. The baseline
airway resistance in all groups was similar before the methacholine
provocation, and these values (units = cmH2O · ml 1 · s 1)
were as follows: Eo+/+ at day 3, 1.5 ± 0.4; Eo+/+ at
day 7, 1.2 ± 0.1; Eo+/+ at day 30, 1.7 ± 0.4; Eo / at day 3, 1.4 ± 0.01; Eo / at
day 7, 1.3 ± 0.2; Eo / at day 30,
2.1 ± 0.7. Peak increases in airway resistance after the
intravenous injection of 125 µg/ml of methacholine are shown. Values
are expressed as means ± SE; n = 5 mice/group.
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Fig. 8.
Differential leukocyte counts in BAL samples at day
30 after an A. fumigatus conidia challenge in A. fumigatus-sensitized Eo+/+ and Eo / groups. BAL cells were
dispersed onto microscope slides and were differentially stained with
Wright-Giemsa stain. A minimum of 15 HPF or 300 cells was examined in
each cytospin. A total of 1 × 105 BAL cells were
cytospun onto each slide to compensate for differences in cell
retrieval from each mouse.
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Fig. 9.
Whole lung interleukin (IL)-10, monocyte chemoattractant
protein-1 (MCP-1)/CCL2, and interferon- (IFN- ) (A) and
IL-13 and C10/CCL6 (B) levels in A. fumigatus-sensitized Eo+/+ and Eo / mice at day 30 after an A. fumigatus conidia challenge. Cytokine and
chemokine levels were measured using specific ELISAs as described in
MATERIALS AND METHODS. Data are expressed as means ± SE; n = 5 mice/group.
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 |
DISCUSSION |
Considering the important role that eotaxin/CCL11 exerts on the
early recruitment of eosinophils during allergic and asthmatic responses (39) and its putative role in attracting Th2
cells (42), this chemokine is an attractive target in
these diseases (9). The peribronchial infiltration of
eosinophils is mediated in part by allergen-specific Th2 cells, and
supernatants from Th2 cells induced eotaxin/CCL11, RANTES/CCL5, and
lung eosinophilia in naive mice lung eosinophilia when administered
intranasally (28). Other experiments showed that
eotaxin/CCL11 was a major link between allergen-specific T cell
activation and the recruitment of eosinophils into the airways
(34). From the present study, it is apparent that
eotaxin/CCL11 regulates eosinophil recruitment at early times after a
soluble A. fumigatus allergen challenge into A. fumigatus-sensitized mice, but its role in eosinophil recruitment
appears to be limited during more protracted responses (i.e., chronic
fungal asthma) to A. fumigatus spores. This finding is
consistent with previous studies in eotaxin-deficient mice in which
eosinophil recruitment was not (47), or only partially (39), inhibited after ovalbumin sensitization and
challenge. Thus the genetic targeting of eotaxin/CCL11 significantly
inhibits, but does not ablate, eosinophil recruitment in the context of acute fungus-induced asthma.
The present study also highlighted that the lack of eotaxin/CCL11 did
not impact the recruitment of T lymphocytes into the airways of
A. fumigatus-challenged mice. It appears that the
development of allergic disease due to Aspergillus is
initially dependent on the movement of eosinophils into the airways of
allergic mice, but other chemokines or factors and T cells then appear
to regulate airway hyperresponsiveness and the other features of fungal
asthma. Two prime candidates are C10/CCL6 and the pleiotropic cytokine IL-13. C10/CCL6 has major effects on the recruitment of eosinophils and
T cells during acute fungal asthma (20), whereas IL-13 is a major effector in the maintenance of all features of chronic fungal
asthma (3, 4). In addition, we have observed that Th2
cells have a prominent role in the development and maintenance of
chronic fungal asthma, and disease resolution only appears in the
context of this disease when Th2 cell recruitment or activation is
inhibited (3, 4).
The observation that experimental fungal asthma proceeds in the absence
of eotaxin/CCL11 presumably reflects the fact that various chemokines,
including MIP-1
/CCL3, C10/CCL6, RANTES/CCL5, and other eotaxins
including eotaxin-2/CCL24 (14) and eotaxin-3/CCL26 (43), have chemotactic effects on eosinophils and Th2
cells during allergic and asthmatic responses (31). In
addition, it has been shown in a number of studies that distinct
functional groups of chemokines cooperate and coordinate the pulmonary
inflammatory response during experimental allergy and asthma (8,
16, 18). Although this possibility was not explored in the
context of the murine models described herein or elsewhere, more recent
clinical data suggest that eotaxin-3/CCL26 rather than eotaxin/CCL11 or eotaxin-2/CCL24 sustains eosinophil recruitment to asthmatic airways in
the later stages after allergen challenge (1).
In conclusion, the present study demonstrates that eotaxin/CCL11 has a
major role in the recruitment of eosinophils into the airways during
early allergic responses to A. fumigatus, but its role is
limited during more chronic responses to this fungus. In addition, the
lack of eotaxin/CCL11 did not affect the recruitment of T cells to the
airways in either model of Aspergillus-induced disease.
Considering these findings, it is probable that the targeting of
eotaxin/CCL11 during A. fumigatus allergen or conidia
challenge may be of limited utility. However, these findings do not
rule out the therapeutic benefit that may be obtained with a specific CCR3 antagonist (2, 41) that would block the action of all eotaxins and other CCR3 agonists.
 |
ACKNOWLEDGEMENTS |
This work was supported, in part, by funding from the American Lung Association.
 |
FOOTNOTES |
Address for reprint requests and other correspondence:
C. M. Hogaboam, Dept. of Pathology, Univ. of Michigan
Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602 (E-mail: hogaboam{at}med.umich.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 8, 2002;10.1152/ajplung.00341.2001
Received 27 August 2001; accepted in final form 5 February 2002.
 |
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