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From the Department of Pathology,*
University of
Michigan Hospitals, Ann Arbor, Michigan; the Departments of Pathology
and Laboratory Medicine
and Pulmonary
Medicine,
Veterans Affairs Medical Center,
Ann Arbor, Michigan; and the Childrens
Hospital,§
Harvard Medical School,
Boston, Massachusetts
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Abstract |
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in the type-1 response, and enhanced
interleukin-5 and interleukin-13 in the type-2 response. Peripheral
blood leukocytosis was also enhanced in the type-1 but not the type-2
response. These findings suggest that CCR1 agonists contribute to
multiple immunoinflammatory events in the type-1 granulomatous response
with natural killer cell accumulation being particularly sensitive to
CCR1 disruption. Although functional efficacy of granulomas may be
altered, chemokine redundancy and cytokine reserve seem to make
the bulk of the exudative response resistant to CCR1
disruption.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, MIP-3, MIP-5,
RANTES, MCP-3, MIP-1, and mC10.3,6
Previous studies
using CCR1 knockout (CCR1-/-) mice have reported abrogated
inflammation, altered hematopoiesis, and delayed cardiac graft
rejection.7-9
It has also been reported
that CCR1-/- mice display exacerbated inflammation and associated
enhancement of selected parameters of Th1 immunity in a murine model of
nephrotoxic nephritis.10
The latter findings suggested
that Th1 responses may be favored in CCR1-/- knockout mice, but other
reports indicate that agonists of CCR1 promote Th1
responses.11,12
The in vitro studies of Lukacs
and colleagues13
demonstrated that MIP-1, a CCR1
ligand, had different effects on Th1 and Th2 cytokines during the
primary inductive phase versus the memory/secondary
response. Thus, conflicting results might arise depending on the type
of response and the stage at which it is examined.
As yet, there is no systematic study of the effect of CCR1 knockout on
secondary Th1 and Th2 responses. In an attempt of clarify the role of
CCR1 in these responses, we examined the effect of CCR1 knockout on
defined models of polarized type-1 and type-2 pulmonary granulomatous
inflammation elicited by antigens derived from Mycobacteria
bovis and ova of the helminthic parasite, Schistosoma
mansoni.14,15
The findings indicate that although
CCR1 knockout had no effect on gross lesion size in either the type-1
or type-2 response, there was evidence that CCR1 regulated levels of
circulating leukocytes and was required for recruitment of lymphoid
subpopulations. Specifically, natural killer (NK) cells were reduced in
CCR1-/- mice with type-1 lesions. In addition, their draining lymph
nodes displayed partial impairment of Th1 cytokines similar to that
described in CCR2-/- mice.16
Conversely, there was
enhancement of Th2 cytokines during the type-2 response. Lymph node
changes could not be attributed to altered proportions of lymphoid
populations; therefore the effect was likely because of functional
changes. These findings would suggest that CCR1 has nonredundant
functions under particular circumstances, such as in responses that
depend on NK cells. In addition, CCR1 likely shares redundant functions
with other chemokine receptors that promote the secretion of interferon
(IFN)-.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CCR1 knockout mice on 129Sv X B6 background were generated from 129Sv strain embryonic stem cells using targeting vectors as previously described.7 Control animals consisted of age-matched nonmutant 129Sv X B6 F2 mice. Mice were maintained in isolator cages under specific pathogen-free conditions and provided with food and water ad libitum.
Sensitization and Granuloma Induction
Types 1 and 2, secondary antigen-bead granulomas were generated as previously described.17 Briefly, mice were sensitized by subcutaneous injection of 20 µg M. bovis-purified protein derivative (PPD; Department of Agriculture, Veterinary Division, Ames, IA) incorporated into 0.25 ml of complete Freund’s adjuvant (product number F-5881; Sigma, St. Louis, MO) or 3,000 S. mansoni eggs suspended in 0.5 ml of phosphate-buffered saline (PBS). Fourteen to 16 days later PPD and schistosome egg-sensitized mice were respectively challenged by tail vein with 6,000 Sepharose 4B beads (in 0.5 ml PBS) covalently coupled to PPD or to soluble schistosome egg antigens (SEA) obtained from the World Health Organization, Geneva, Switzerland.
Granuloma Dispersal and Draining Lymph Node Culture
Groups of mice were killed at 1, 2, 4, and 8 days of granuloma formation. After perfusion with cold RPMI, lungs excluding trachea and major bronchi were excised. The right upper lung of each mouse was snap-frozen in liquid N2 for mRNA isolation. The left lower lobe was postinflated and formalin-fixed. The remaining lung lobes were placed in cold RPMI medium then granulomas were isolated and dispersed as previously described.14,18 For differential counting, duplicate cytospin preparations were prepared from the remaining dispersed granuloma cells and stained with Wright’s stain. Blood was also collected from each animal and total white cell count and differential performed.
Mediastinal lymph nodes were collected at the time of lung harvest and teased into single cell suspension. After washing, the cells (5 x 106/ml) were cultured for 24 hours in RPMI-1640 medium (JRH Biosciences, Lenexa, KS) containing 10% fetal bovine serum (Intergen, Purchase, NY), 10 mmol/L glutamine, and 100 mg/ml streptomycin and 100 U/ml penicillin (RPMI-fetal bovine serum) in the presence or absence of 5 µg/ml of PPD or SEA. Supernates were collected by centrifugation at 1,000 x g for 10 minutes and stored at -45°C.
Granuloma Measurement
Granulomas were measured blindly from formalin-inflated lungs that were paraffin-embedded, sectioned, and then stained with hematoxylin and eosin. Granuloma area was measured by computerized morphometry. A minimum of 20 lesions was measured per lung.
Southern Blot Analysis
Genotyping was confirmed by Southern analysis of genomic DNA as previously described,7 with the exception that the SacI restriction enzyme was used to generate DNA fragments. Characteristic, 5-kb wild-type and 7-kb mutant gene fragments were identified by specific probe hybridization.
Flow Cytometry
Dispersed granulomas and mediastinal lymph node suspensions were subjected to flow cytometry using one- and two-color fluorescent analysis. For the staining of CCR1 and CCR2b chemokine receptors, cells (1 x 106) were fixed and permeabilized with Cytofix/Cytoperm (Pharmingen, San Diego, CA). After the permeabilization step, cells were incubated with a control antibody (goat IgG; Zymed Laboratories, Inc., San Francisco, CA) or polyclonal antibodies against the cytoplasmic tail of murine CCR1 or CCR2b (goat IgG; Santa Cruz Biotechnology Inc., Santa Cruz, CA). After 30 minutes at 4°C, cells were washed and stained in the dark for 30 minutes with fluorescein isothiocyanate-labeled anti-goat IgG (Santa Cruz Biotechnology Inc.). For dual staining of cell surface markers and chemokine receptors, cells were first incubated with phycoerythrin-labeled monoclonal antibodies to CD3, CD4, CD8, CD19, pan-NK (DX5), or NK1.1 (PK136) (Pharmingen), and then stained with antibodies against the cytoplasmic tail of mouse chemokine receptors by the intracellular procedure mentioned above. Stained cells were analyzed using a FACScan flow cytometer (Becton Dickinson, Mountain view, CA). Lymphocyte population was gated using forward and side scatter characteristics. Cells (10,000 to 20,000) were analyzed and data were processed with CellQuest software (Becton Dickinson).
Cytokine Measurement
Interleukin (IL)-2, -5, and -13, MIP-1, and IFN- were
measured by enzyme-linked immunosorbent assay using commercially
available reagents (Pharmingen and R&D Systems, Minneapolis, MN);
sensitivities ranged from 10 pg/ml to 50 pg/ml. Commercially available
recombinant murine cytokines served as standards in all assays
(Genzyme, Cambridge, Preprotech Inc., Rocky Hill, NJ, and R&D Systems).
Statistics
The Student’s t-test (two-tailed) was used to compare control with experimental groups. Values of P > 0.05 were considered to indicate lack of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice with knockout of the CCR1 gene reportedly display impaired granuloma formation in response to primary challenge with S. mansoni eggs.8 In the present study we tested the capacity of CCR1-/- mice to generate type-1 and type-2 granulomas under anamnestic conditions using Ag bead challenge of presensitized mice. Anamnestic type-1 and type-2 inflammatory responses can be studied in mice by sensitizing with mycobacterial PPD or soluble SEA Ags, followed 2 weeks later by respective intravenous challenge with agarose beads covalently coupled to PPD or SEA. In these models, the antigen-coated beads embolize to the lung where they induce pulmonary granulomas mediated by type-1 and type-2 cytokines.14,15,19
Mice with targeted disruption of the CCR1 gene were generated as
previously described.7
Southern blot analysis and direct
flow cytometric detection was used to confirm CCR1 gene disruption.
Wild-type mice displayed a normal 5-kb SacI digest fragment
whereas knockout mice showed a 7-kb mutant form. In addition, direct
staining of splenocytes indicated CCR1 protein expression was
essentially ablated, whereas an independent CC chemokine
receptor, CCR2b, was preserved (Figure 1)
.
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, CCR1-/- mice had no significant
change in gross lesion dimensions under anamnestic conditions.
Histologically, lesions seemed similar in the wild-type and mutant
strains (Figure 3)
. Likewise, when
differential analysis was performed on dispersed lesions there was no
statistically significant difference in leukocyte composition, however
it was noted there was a trend to enhanced eosinophils in type-2 SEA
bead lesions on day 8 (Figure 4)
.
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. As expected, gating analysis
indicated CCR1 was distributed among lymphoid and nonlymphoid cells
(data not shown).
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Leukocyte differential analysis in the Wright-stained cytospin
preparation represents only a gross monitor of major leukocyte
populations. Because lymphoid subpopulations have been reported to
display differential expression of chemokine receptors,2,4
we analyzed lymphocyte subpopulations in dispersed granuloma cells
by one- and two-color flow cytometry to detect potential
changes because of CCR1 deficiency. A representative flow cytometric
analysis of the proportions of CD4+ (T helper),
CD8+ (T cytotoxic), and CD19 (B cells) in day 4 types-1 and -2
granulomas is shown in Figure 6
. Knockout
of CCR1 did not significantly affect these populations.
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. Moreover, there was a clear
effect of CCR1 deficiency with type-1 lesions of CCR1-/- mice
displaying significantly decreased levels of NK cells. This finding was
repeated using an independent NK1.1-specific antibody and dual staining
analysis indicated that 60% of NK1.1+ cells from type-1 lesions bore
CCR1 (data not shown). The latter was not surprising because there are
several published reports that demonstrate NK cells display strong
chemotactic responses to CCR1 ligands.20,21
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In addition to their chemotactic function, ligands of CCR1 are
reported to have a co-stimulatory effect on lymphocyte proliferation
and cytokine production.22
In this regard, we cultured
draining mediastinal lymph nodes in the presence of specific Ag then
measured the levels of cytokines produced. Two representative
Th1-associated cytokines, IFN- and IL-2, and two Th2-associated
cytokines, IL-5 and IL-13, were measured during the course of granuloma
formation and are shown in Figure 8
. Both
CCR+/+ and CCR1-/- mice displayed polarized type-1 and type-2
cytokine profiles. However, IL-2 and IFN- levels were reduced in
CCR1-/- mice during the type-1 response. There was even some decrease
in the already low levels of IFN- produced during the type-2
response on day 8. Conversely, there was modest but significant
augmentation of Th2-associated cytokines on days 2 and 4 during the
type-2 response. These altered cytokine profiles could not be explained
by changing proportions of lymphoid populations because flow cytometric
analysis of the dispersed nodes from CCR+/+ and CCR1-/- mice revealed
comparable percentages of CD3+CD4+, CD3+CD8+, and
CD19+ cells. NK cells were consistently <1% of the draining lymph
nodes of all mice (data not shown).
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Because CCR1 ligands such as MIP-1 are reported to regulate
lymphocyte recirculation and hematopoiesis,23-25
we
monitored blood leukocyte levels and composition. Figure 9
shows baseline and postchallenge blood
leukocyte numbers in control and CCR1-/- mice. Baseline levels were
comparable in unchallenged CCR+/+ and CCR1-/- mice. After PPD bead
challenge total leukocyte counts achieved higher levels in CCR1-/-
mice on days 2 and 4. This enhancement did not occur during the type-2
response to SEA bead challenge, suggesting that blood leukocyte levels
were regulated differently in the two responses. When differential
leukocyte analysis was performed the increased populations included
lymphocytes, neutrophils, and monocytes, indicating that the observed
increase in total counts in the type-1 response extended to lymphoid
and nonlymphoid populations.
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in draining lymph node cultures during the course of type-1
and type-2 granuloma formation. As shown in Figure 10
, MIP-1 was produced to a much
greater degree in the PPD (type-1) as compared to the SEA (type-2)
lymph node cultures. This was especially true during the early phase (1
to 2 days) of the response. It should be noted that levels of MIP-1
production were similar in CCR1-/- mice (data not shown). Thus, the
time course and differential production of MIP-1 correlated well
with the greater observed effects of CCR1 deficiency on lymph node
events and blood leukocyte levels.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, MIP-3, MIP-5, RANTES,
MCP-3, MIP-1, and mC10.3,6
Consequently, it is
potentially important in leukocyte recruitment events. Previous studies
have reported both abrogation and enhancement of inflammatory responses
by CCR1 disruption. These varied responses are most likely related to
the different experimental models and target organs that were examined.
Specifically, abrogation occurred in models of acute lung injury and
cardiac allograft rejection,7,9
whereas exacerbation was
reported in a model of nephrotoxic nephritis.10
In yet
another report Gao and colleagues8
demonstrated impaired
primary schistosome egg granuloma formation in CCR1-/- mice, that was
associated with enhanced IFN- production and reduced IL-4
production. In the present report, using models of highly polarized
type-1- and type-2 cell-mediated granuloma formation, CCR1 knockout did
not limit the ultimate extent of the inflammatory response. However, we
did identify subtle changes indicating that CCR1 was contributing in
part to local cellular recruitment, Th1/Th2 cytokine balance, and
hematopoiesis.
With regard to cellular recruitment, we identified specific impairment
of NK cell accumulation in type-1 granulomas, which normally harbor a
significant component of these cells. However, the reduction of these
cells did not significantly limit the overall extent of the
inflammatory response indicating that these cells are not essential to
the type-1 granuloma. We presently postulate that the NK cell component
represents a vestigial background response that is primarily
overshadowed by the activity of Ag-specific Th1 cells. However, in
responses in which NK cells provide a greater contribution, the effect
of CCR1 knockout may be more profound, possibly explaining some of the
conflicting effects of CCR1 knockout. We have identified potential CCR1
agonists produced during lung granuloma formation, such as MIP-1,
RANTES, and MCP-3.17,26,27
Although these chemokines may
have a direct role in CCR1-mediated NK cell recruitment, we cannot rule
out indirect effects. For example, CXCR3 ligands can also mediate NK
cell chemotaxis20,21
and CCR1 knockout may impair
production of CXCR3 ligands, thereby indirectly impairing NK cell
recruitment. Other indirect effects causing reduced NK cell
accumulation could include impaired NK proliferation or enhanced
apoptosis.28
Also, our understanding of lymphocyte
migration efficiency in vivo is limited. Both NK and Th1
cells are reported to respond to CCR1 and CXCR3 ligands, but if NK
cells require greater stimulation for efficient migration then they
could be at a disadvantage if a chemokine receptor is compromised.
Our analysis revealed that CCR1 contributed to Th1/Th2 cytokine balance
in draining lymph node cultures. In three separate experiments,
knockout was associated with impaired Th1 and enhanced Th2 cytokines,
which did not compromise the type-1 inflammatory response although we
noted a tendency to enhanced eosinophil recruitment in type-2 lesions.
Our results differ from studies of Gao and colleagues8
who
reported impaired inflammation, augmented IFN-, and reduced Th2
cytokines on primary challenge with S. mansoni eggs. This
discrepancy is likely because of different experimental conditions,
since that study did not examine the anamnestic secondary response to
S. mansoni Ags. Because the granulomatous response to
S. mansoni eggs shifts from a Th0/Th1 to a Th2-dominant
response,29
it suggests that the early primary stage is
more sensitive to CCR1 deficiency. Likewise, it would relate to the
finding of Lukacs and co-workers26
who reported that the
primary response to S. mansoni eggs is more dependent on the
CCR1 ligand, MIP-1, than the secondary response. In any case, our
findings are fully consistent with several in vitro studies
indicating that CCR1 ligands support Th1 cytokine
production.11-13,30
Furthermore, the observed enhancement
of type-2 cytokines could result from alleviation of IFN- or
chemokine-mediated cross-regulation.17,31
Taken together,
the in vivo and in vitro findings argue that CCR1
ligands tend to promote Th1 cytokine production.
In CCR1-/- mice we observed enhanced blood leukocytosis during
type-1 but not type-2 granuloma formation. The difference was likely
related to the greater production of CCR1 agonists such as MIP-1
during Th1 responses.17,32
The elevation itself is
consistent with a recent in vitro study of Broxmeyer and
colleagues25
demonstrating that CCR1 agonists inhibit
granulocyte-monocyte colony stimulating factor (GM-CSF)-mediated
myeloid progenitor cell mobilization. Because granuloma induction is
associated with release,33
CCR1-/- mice might be
predicted to have elevated blood leukocyte counts during granuloma
formation. Interestingly, we have observed a virtually identical
pattern of leukocytosis that occurs in MIP-1 knockout mice. These
findings would be consistent with the notion that CCR1 and agonists
regulate hematopoietic dynamics. However, an additional
explanation for the elevated blood leukocytes might include hampered
lymphocyte recirculation causing lymphocytes to accumulate in the
circulating pool as lymphocytes were an important component of the
increased leukocytes in blood. This could reflect impaired CCR1
agonist-mediated trafficking to secondary lymphoid tissues because the
CCR1 agonists MIP-1 and MIP-1ß have been shown to be important for
T cell emigration to lymph nodes.23
Finally, a comparison should be made between the effect of CCR1 and
CCR2 knockout. The latter primarily impaired early phase
monocyte/macrophage and to some extent CD4+ T
cell accumulation at sites of granuloma formation,16,34
indicating different recruitment roles for CCR1 and CCR2 agonists.
However in both types of mutants, overall granuloma formation was
ultimately established, despite transient or selective defects.
Interestingly, CCR2 knockout was similarly associated with impaired
IFN- production by draining lymph node cultures, fully consistent
with in vitro studies demonstrating that both CCR1 and CCR2
agonists can promote IFN- production.13
In addition, in
preliminary studies we have noted significantly reduced MIP-1
in lymphoid cultures of CCR2-/- mice suggesting that the production
of CCR1 agonists may be dependent on upstream CCR2 ligation.
In summary, although CCR1 disruption failed to significantly limit polarized forms of pulmonary granuloma formation, underlying defects were identified primarily in the type-1 response to mycobacterial Ags, consisting of impaired NK cell recruitment, diminished type-1 cytokine production and altered blood leukocyte dynamics. These findings suggest that chemokine redundancy and cytokine reserve make the anamnestic T cell-mediated inflammatory response resistant to CCR1 disruption. However, CCR1 clearly contributes to local, regional, and systemic immunoinflammatory events.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health-National Institute of Allergy and Infectious Diseases grant AI43460 and in part by National Institutes of Health grants HL52773 and HL56306. Dr. Curtis is a Career Investigator of the American Lung Association of Michigan. Schistosome life stages were supplied through National Institutes of Health-National Institute of Allergy and Infectious Diseases Contract N01-AI-55270.
Accepted for publication August 21, 2000.
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