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Chemokine Biology Laboratory, Department of Molecular BioSciences, University of Adelaide, Adelaide, South Australia, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and muMIP-2 in the
inflammatory response mounted against the bacteria Salmonella
enteritidis and the Sacchromyces cerevisiae cell
wall component, zymosan. Leukocyte extravasation was monitored in
murine s.c. air pouches. Both agonists induced accumulation of
leukocytes in a dose- and time-dependent manner, with the response
peaking after 4 h and declining thereafter. The inflammatory
exudate comprised mainly neutrophils; however, an increase in
eosinophil accumulation was also observed in response to zymosan. The
production of both muMIP-1 and muMIP-2 increased with time in
response to both the agonists, although production was more sustained
in response to the bacteria. Prior treatment of mice with neutralizing
Abs against muMIP-1 or muMIP-2, either alone or in combination,
failed to attenuate the accumulation of leukocytes in response to the
agonists. In contrast, the anti-muMIP-2 Abs significantly inhibited
leukocyte recruitment in response to S. enteritidis in
complement-deficient mice. Taken together, these data show that while
muMIP-1 and muMIP-2 are produced in response to phagocytosis of
micro-organisms in s.c. tissue, under these circumstances components of
the complement pathway appear to play a dominant role in the
recruitment of neutrophils. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The chemokine gene superfamily comprises dozens of small chemoattractant cytokines that play a key role in a variety of immunoregulatory and proinflammatory responses (8, 9, 10, 11). Chemokines are basic, heparin-binding, low molecular mass (8- to 12-kDa) proteins containing a characteristic cysteine signature motif. Assignment of chemokines to subdivisions is based upon primary amino acid structure and the nature of the cysteine motif, generating two major and two minor families. The major subfamilies are designated according to the presence (CXC) or the absence (CC) of an intervening amino acid between the two cysteine residues nearest the N terminus of these proteins. The CXC family can be further subdivided into two groups: those that contain a glutamate-arginine-lysine tripeptide motif proceeding the CXC signature (ELR), and those that do not contain the ELR motif (non-ELR).
Murine macrophage-inflammatory protein
(muMIP)3 2 and
muMIP-1 are two chemokines that have chemotactic activity toward
neutrophils in vitro (12, 13) and are involved in
neutrophil extravasation in vivo (14, 15). In previous
reports we have demonstrated that neutralizing endogenous muMIP-2 and
muMIP-1 activity generated in response to TNF- leads to a
dramatic reduction in the number of neutrophils recruited into s.c. air
pouches in mice (14, 15). Moreover, blocking CXCR2, the
receptor for muMIP-2, with an antagonist inhibits neutrophil
recruitment in vivo in response to TNF-, IL-1
, and LPS
(15). Together, these data indicate that muMIP-2 and
muMIP-1 play a key role in neutrophil extravasation to s.c. tissue
in response to proinflammatory molecules.
We have previously shown in vitro that human neutrophils produce IL-8
(a homologue of muMIP-2) and MIP-1 in response to challenge by
agents that induce phagocytosis, including several of microbial origin,
such as zymosan, Salmonella typhimurium, Pseudomonas
aeruginosa, and Staphylococcus aureus (16, 17). However, while the results of previous studies using
soluble agonists such as TNF- and IL-1 have defined a role for
muMIP-2 and muMIP-1 in neutrophil extravasation during acute
inflammation in vivo (14, 15, 18), there is as yet little
evidence supporting a similar role for either of these chemokines in
acute inflammation induced by microbial agents. In the present study we
have investigated a potential role for these two chemokines in vivo in
the recruitment of neutrophils into s.c. air pouches in response to
phagocytic agents of microbial origin.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to 8-wk-old male and female BALB/c mice were obtained from
the Central Animal House at the University of Adelaide (Adelaide,
Australia). Six- to 8-wk-old B10.D2/O2Sn (C5-deficient) and B10.D2/N2Sn
mice (wild-type controls) (19, 20, 21) were purchased from the
Animal Resource Centre breeding facility (Perth, Australia). All
other reagents used in this study were of molecular biological grade
and obtained from Sigma (St. Louis, MO). Salmonella
enteritidis strain 11RX (22) was obtained from frozen
stocks within the Department of Microbiology and Immunology (University
of Adelaide). The protein A-Sepharose-purified anti-muMIP-1,
anti-muMIP-2, and control IgG Abs used were raised in rabbits in
this laboratory (14, 18) using full-length synthetic
muMIP-1 and muMIP-2 that were chemically synthesized as
previously described (23, 24). Each of the
polyclonal sera was tested for cross-reactivity against other
chemokines (JE, muMIP-2, KC, muMIP-1, muMIP-1, muRANTES, C10,
muTCA-3, and murine lymphotactin) in direct ELISA and Western
blot assays. No cross-reactivity was observed.
Leukocyte migration in s.c. air pouches
Air pouches were raised on the dorsum of mice by s.c. injection of 2.5 ml of sterile air on days 0 and 3 as previously described (14, 18, 25). All experiments were conducted on day 6. On day 6, overnight bacterial cultures were centrifuged (3000 rpm, 10 min) and washed in endotoxin-free (E/F) PBS. The number of bacteria was determined by spectrophotometric absorbance (A600). Differing amounts of bacteria or zymosan, in the case of dose-response experiments, were injected in 1.0-ml volumes into air pouches. At the appropriate time points, mice were euthanased, and the residual liquid was removed from the air pouch. The air pouches were then washed twice with 2.0 ml of PBS. The exudate was centrifuged, the supernatants were removed for ELISA analysis, and the cell pellets were resuspended in 1.0 ml of PBS and counted in white blood cell-counting fluid (0.01% gentian violet and 1.5% acetic acid) using a hemocytometer. Two hundred thousand cells were centrifuged onto microscope slides at 500 rpm for 5 min using a cytospin centrifuge (Shandon, Lab Supply, Adelaide, Australia). The slides were air-dried and then stained with Diff-Quik (Sigma/Aldrich, Castle Hill, Australia) to allow quantitation of the granulocyte and mononuclear cell populations.
Passive immunization with anti-chemokine Abs
Passive immunization was achieved by injecting 300 µg of
either protein A-Sepharose-purified rabbit anti-muMIP-2 or
anti-muMIP-1 Abs or the equivalent amount of IgG purified from a
preimmune rabbit into the peritoneal cavity of mice the evening before
injection of the agonists into the air pouches, as previously described
(14, 18).
Quantitation of the levels of immunoreactive muMIP-1 and muMIP-2
The levels of muMIP-1 and muMIP-2 in pouch supernatants were
quantified by sandwich ELISA as previously described (14, 18). Briefly, high binding 96-well microtiter plates (Costar,
Cambridge, MA) were coated with 100 µl of capture Ab (diluted 1/3,000
in 0.1 M NaHCO3, pH 8.3) and incubated at 4°C
overnight. Plates were washed twice with PBS/Tween 20 (0.2%
polyoxyethylene-sorbitan monolaurate; Sigma) and blocked with 200 µl
of PBS/3% BSA for 1 h at 37°C. Plates were washed twice,
chemokine standard or sample was added at 100 µl/well, and the plates
were incubated for 90 min at 37°C. Wells were washed twice, then 100
µl of detection Ab (diluted 1/10,000) was added and incubated for 90
min at 37°C, followed by two washes. Biotin-conjugated
anti-rabbit F(ab')2 (Amersham,
Arlington Heights, IL) was then added at 100 µl/well and incubated
for 45 min at room temperature. Plates were washed twice, and 100 µl
of streptavidin-HRP conjugate (Amersham) was added per well. Plates
were incubated for 30 min at room temperature, then washed four times
in PBS/Tween 20. Peroxidase reactions were developed by the addition of
200 µl/well Fast-O-phenylenediamine dihydrochloride
substrate (Sigma), and the reaction was terminated by the addition of
50 µl of 3 M HCl. Absorbance was determined at 485 nm on a Biolumin
96-well plate reader (Molecular Dynamics, Sunnyvale, CA) using
Xperiment software (Molecular Dynamics).
Statistical analysis
The alternate t test was used as indicated in the figure legends for all statistical analyses. Results were considered significant at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Air pouches were formed on the backs of 6- to 8-wk-old BALB/c mice
as described in Materials and Methods. Increasing numbers of
bacteria, in the case of Salmonella enteritidis, and
increasing amounts of zymosan or a fixed volume of the diluent (E/F
PBS) were injected into the air pouches, and the cellular exudate was
collected and counted after 4 h (Fig. 1
). Low numbers of leukocytes were
present in the pouches at time 0, with no significant increase in
leukocyte accumulation following injection of the diluent after 4
h (see Fig. 2). Injection of S.
enteritidis induced a significant increase in leukocyte
accumulation after 4 h at 1 x 104
CFU/pouch, the lowest level tested (Fig. 1). This accumulation of
leukocytes reached maximal levels in response to 1 x
107 CFU/pouch, the highest infectious dose
tested. Zymosan generated a similar dose response to S.
enteritidis (Fig. 1), with significant infiltration of leukocytes
at 1.0 µg/pouch and maximal response at 100 µg/pouch.
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Low numbers of leukocytes were present in the air pouch at time 0, with
no significant increase in leukocyte accumulation throughout the time
course following injection of the diluent (up to 24 h). By 1
h postadministration of zymosan, an increase in the number of
leukocytes was observed in the air pouches. This response increased at
2 h postinjection, as did the response to S.
enteritidis (see Fig. 2). Maximal accumulation of leukocytes was
observed at 4 h postinjection, at which time the responses to both
zymosan and S. enteritidis were equivalent. Twenty-four
hours after administration of the two agonists leukocyte numbers were
significantly reduced, demonstrating the transient nature of the
inflammation generated by the agonists. The maximal numbers of
leukocytes accumulating are similar to those previously reported using
zymosan (26) and Porphyromonas gingivalis
(27).
Pouch exudate cells from the 2 and 4 h points were differentially
stained to determine the nature of the cell types in the infiltrate
(Figs. 3, A and B).
In the control group, the resident population of cells was
predominantly neutrophils with significantly lower, but there was
approximately equal representation of eosinophils and macrophages at
2 h (Fig. 3A). This profile was altered by the
administration of zymosan. At the two doses examined (100 and 300
µg), a significant increase in the relative percentage of eosinophils
compared with PBS was seen, with approximately equal numbers of
eosinophils and neutrophils comprising the majority of the infiltrate.
Cells from the zymosan dose of 1.0 mg were unable to be identified
because the level of phagocytosis of zymosan microcrystals distorted
cellular integrity and staining. S. enteritidis exhibited a
similar profile to zymosan, with increasing doses skewing the profile
toward greater percentages of neutrophils and the percentage of
eosinophils remaining constant.
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B), a shift in the
makeup of the infiltrating populations had occurred, with a general
trend toward a higher percentage of neutrophils in the pouch cavity
(>80%) and with eosinophils comprising a minor population. Chemokine production in s.c. tissue in response to phagocytic agonists
The air pouch exudate supernatants were next examined for the
presence of the chemokines muMIP-1 and muMIP-2 (Figs. 4, A and B). A low
background level of each chemokine was observed in pouch exudates
collected from mice treated with PBS. However, this background level
did not alter with time (data not shown) (14, 15, 18).
High levels of both chemokines were induced by 2 h
postadministration of each of the two agonists. After 4 h,
accumulation of both chemokines in response to S.
enteritidis remained elevated, although lower than the 2 h
levels. By 4 h poststimulation the responses to zymosan had
virtually returned to control levels, whereas responses to S.
enteritidis remained elevated. By 24 h poststimulation the
level of muMIP-1 produced in response to S. enteritidis
was still significantly above the control value, whereas the level of
muMIP-2 had returned to the control level. The levels of both
muMIP-1 and muMIP-2 produced in response to zymosan at 24 h
were not significantly greater than the control values.
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To determine whether either or both muMIP-2 and muMIP-1 were
playing a causal role in leukocyte extravasation in response to
S. enteritidis and zymosan, mice were pretreated with
control IgG, anti-muMIP-2, and/or anti-muMIP-1 IgG. The mice
were passively immunized by i.p. injection of the Abs 16 h before
injection of PBS or suboptimal doses of the agonists into the air
pouches. Neither Ab, alone or in combination, effectively inhibited the
recruitment of leukocytes in response to S. enteritidis or
zymosan. This was not due to lack of persistence of the Abs in the
mice or lack of penetration of the Abs into the s.c. tissue, as ELISAs
conducted to measure the levels of rabbit IgG found elevated levels in
both the peripheral blood and in s.c. air pouch exudate fluid (data not
shown). The results of experiments conducted using 300 µg of Ab and
3 x 104 CFU and 10 µg of S.
enteritidis and zymosan, respectively, are shown in Fig. 5. Of note, the route of administration
of the Abs did not affect the outcome of these experiments, as
coinjection of the Abs and agonists into the air pouches also failed to
inhibit leukocyte recruitment in response to the agonists (data not
shown).
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Reasoning that products of the C' pathway may be strongly
influencing the leukocyte recruitment response, leukocyte extravasation
in response to S. enteritidis and zymosan in B10.D2/O2Sn
mice that are deficient in C5 was investigated. Air pouches were raised
on the backs of these animals as described in Materials and
Methods, and the pouches were injected with either PBS or doses of
S. enteritidis and zymosan that, based on the data shown in
Fig. 1, were suboptimal. In these experiments both zymosan and
S. enteritidis stimulated leukocyte recruitment
into the air pouches formed on the backs of wild-type mice (Fig. 6). In contrast, the effect of these
agonists on leukocyte recruitment, while still greater than the control
levels, was significantly reduced in the C5'-deficient mice.
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To compare the level of production of muMIP-2 and muMIP-1 in
air pouches in wild-type and C5'-deficient mice, pouch exudate
supernatants were subjected to ELISA. Control values for muMIP-1
were essentially the same in both mice (Fig. 8A). Addition of zymosan
increased the level of muMIP-1 above control values; however, no
significant difference in the level of muMIP-1 produced in response
to zymosan was observed in the two types of mice. In contrast, S.
enteritidis induced a larger increase in the level of muMIP-1
than zymosan, and this increase was slightly smaller in the
C5'-deficient mice. The expression of muMIP-2 followed a pattern
similar to that observed with muMIP-1 (Fig. 8B).
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To determine whether muMIP-2 and/or muMIP-1 play an important
role in leukocyte recruitment in response to S. enteritidis
and zymosan in C5'-deficient mice, the mice were pretreated with
control IgG, anti-muMIP-2 IgG, and/or anti-muMIP-1 IgG
16 h before injection of either PBS, S. enteritidis, or
zymosan into air pouches. In these experiments, addition of either
S. enteritidis or zymosan led to accumulation of the
expected number of leukocytes. Prior treatment of the mice with
anti-muMIP-1 IgG had no significant effect on the level of
leukocyte recruitment in response to either agonist (Fig. 9). Prior treatment of the mice with
anti-muMIP-2 IgG exhibited no effect on leukocyte recruitment
induced by zymosan, but significantly inhibited the response to
S. enteritidis. The combination of both anti-muMIP-1
and anti-muMIP-2 IgG inhibited the responses to both S.
enteritidis and zymosan.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in s.c. tissue and have
determined whether the expression of these chemokines plays a causal
role in leukocyte extravastion in response to such agonists. Our
results clearly demonstrate that S. enteritidis, a
Gram-negative intracellular bacterium, and zymosan, a cell wall
component of the yeast S. cerevisiae, rapidly mobilize
leukocytes (predominantly neutrophils) from the peripheral blood into
s.c. tissues and that this recruitment of neutrophils is accompanied by
accumulation of the chemokines muMIP-2 and muMIP-1 at the site of
administration. However, prior treatment of mice with neutralizing Abs
against either chemokine or both chemokines simultaneously had no
effect on the level of leukocyte recruitment in response to S.
enteritidis and zymosan. Additional experiments demonstrated that
the major regulators of leukocyte recruitment under these conditions
are components of the C' pathway, and that in C5-deficient mice,
muMIP-2 and muMIP-1 assume an important role in neutrophil
extravasation in response to S. enteritidis and zymosan.
The results of our previous studies have indicated that muMIP-2 and
muMIP-1 individually play a causal role in the recruitment of
neutrophils to s.c. tissue in response to a range of soluble agonists,
including TNF-, IL-1, and staphylococcal superantigens (14, 15, 18). These two chemokines accumulate rapidly in response to
the above agonists, and neutralization of their activity in vivo, with
the same Abs as those used in the present study, significantly reduced
neutrophil recruitment. Other lines of evidence also support the idea
that these two chemokines are involved in neutrophil extravasation in
vivo (28, 29, 30, 31).
Failure of the anti-chemokine Abs to inhibit zymosan- and S.
enteritidis-induced leukocyte accumulation cannot be adequately
explained by a failure of the Abs to neutralize their targets in vivo.
We have previously used the same Abs to define a role for muMIP-2 and
muMIP-1 in neutrophil recruitment in vivo in response to agents such
as TNF- and IL-1 (14, 15, 18). The failure of the
Abs to inhibit the response is also unlikely to be related to the
levels of chemokines produced, as similar levels of the two chemokines
were detected in the air pouches regardless of whether soluble or
particulate agonists were used (14, 15, 18). Based on
these arguments and because of the known role of C' in innate immunity
directed against microbial agents, we investigated the possibility that
the action of C' may have been providing a dominant signal in this
system that was overriding the effect of muMIP-2 and/or muMIP-1 in
the leukocyte recruitment response under these circumstances.
The C5'-deficient mouse used in this study, the B10.D2/O2Sn mouse, has
a deficiency in C5 and, therefore, in the production of C5a (32, 33), the major leukocyte chemotactic factor produced following
C' activation (6, 7). Using these mice we were able to
show that anti-muMIP-2 and anti-muMIP-1 Abs inhibit
neutrophil recruitment induced by either zymosan or S.
enteritidis. We can therefore propose the following model with
respect to this observation. Activation of C' by both S.
enteritidis and zymosan via the alternative pathway rapidly leads
to the production of C5a, a highly effective neutrophil chemoattractant
(6, 7, 34). This leads to the rapid and substantial
recruitment of neutrophils into the air pouch. Injection of S.
enteritidis and zymosan into the air pouch would also lead to
production of IL-1 and TNF- (26, 35, 36, 37, 38) and
chemokine gene expression (38, 39) as previously shown at
other anatomical sites such as the peritoneal and pleural cavities,
probably by macrophages present in the s.c. air pouches and connective
tissue cells surrounding the air pouch (35, 40). However,
this response would be slower than that mediated by C' because of the
requirement for transcription and translation the cytokine and
chemokine genes. It therefore appears likely that there are two major
phases of generation of the chemotactic factors that are involved in
the neutrophil-recruiting response to S. enteritidis and
zymosan: an initial, rapid phase that results in the generation of C5a,
which appears at least in this case to be sufficient to drive the
inflammatory response, and a second, slower phase, which produces
chemotactic factors such as chemokines. This second phase appears to be
redundant at least under the conditions tested here. This explains why
the anti-chemokine Abs failed to inhibit leukocyte recruitment in
wild-type animals. In contrast, when soluble agonists are used in these
studies, C' is not activated (either at all or to the same extent), and
cell recruitment is therefore significantly more dependent on the
production of chemokines such as muMIP-2 and muMIP-1 as we have
previously shown for TNF- and IL-1 (14, 15).
The major cell type accumulating in s.c. tissue in response to
inflammatory stimulation is the neutrophil (Refs. 14, 15 ,
and 41 and the present study). We have previously
postulated that these cells can further contribute to inflammatory cell
accumulation by releasing chemokines and other chemoattractants
(16, 17, 42). Of particular relevance to the present
study, we have previously shown that neutrophils incubated with
Gram-negative bacteria, such as S. typhimurium and P.
aeruginosa, produce both IL-8 (muMIP-2 homologue) and MIP-1
(16). In contrast, when incubated with nonreplicative
phagocytic agonists such as zymosan and the inflammatory microcrystals,
monosodium urate and calcium pyrophosphate dihydrate,
neutrophils release only IL-8, and in fact, the release of MIP-1 in
response to TNF- is inhibited (16, 17). This does not
appear to be the case in the in vivo setting investigated in the
present study, as injection of zymosan into the air pouch led to the
production of levels of muMIP-1 similar to those produced in
response to S. enteritidis.
Our data also suggest that under the conditions tested, C' activation
is not required either directly or indirectly for the generation of
muMIP-2 or muMIP-1 at this peripheral site. The relative levels of
muMIP-2 and muMIP-1 generated in the s.c. air pouches in wild-type
and C5'-deficient mice were not statistically different. Furthermore,
since the levels of these two chemokines in the wild-type and
C5'-deficient animals were equivalent, even though fewer leukocytes
accumulated in the s.c. air pouches in C5'-deficient mice, it appears
that muMIP-2 and muMIP-1 generation in the air pouch chiefly depends
on resident cells rather than infiltrating leukocytes. This is somewhat
in contrast to our previous findings in which leukocytes accumulating
in pouch exudates in response to TNF- and Staphylococcal
superantigens contained elevated levels of muMIP-2 and muMIP-1 mRNA
compared with leukocytes collected from air pouches injected with PBS
(14, 18).
In summary, we have determined that in response to microbial
stimulation in s.c. tissue in vivo, the chemokines muMIP-2 and
muMIP-1 are produced, but appear to be functionally redundant, at
least under the conditions tested, due to the activation of C'. This
observation is certainly in keeping with the substantial known
redundancy that exists within the immune system. It is possible that
the production of muMIP-2 and muMIP-1 under these circumstance may
play a more subtle role than that of attraction of large number of
neutrophils; however, it is also possible that these genes have evolved
to play an important role in innate immune defense against microbial
agents that can evade or at least minimize C' activation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Shaun R. McColl, Chemokine Biology Laboratory, Department of Molecular BioSciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
3 Abbreviations used in this paper: muMIP, murine macrophage-inflammatory protein; E/F, endotoxin free.
Received for publication November 13, 2000. Accepted for publication February 15, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in human neutrophils. J. Immunol. 162:474.. J. Immunol. 19:3595.
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and IL-6 by adherent spleen cells after the stimulation with lipopolysaccharides from Salmonella enteritidis strain. Immunopharmacol. Immunotoxicol. 18:433.[Medline]
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