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Short Communications |
-/- and MCP-1-/- Mice
****
From the Department of Microbiology and Immunology,*
Burn and Shock Trauma Institute,
the
Departments of Surgery
and Cell
Biology, Neurobiology, and Anatomy,
Immunology
and Aging Program,**
Loyola University Medical Center,
Maywood, Illinois; the Department of Immunology,¶
Schering-Plough Research Institute, Kenilworth, New Jersey; and the
Department of Adult Oncology,||
Dana-Farber Cancer
Institute, Boston, Massachusetts
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1) and monocyte chemotactic protein-1 (MCP-1) are
abundant in acute wounds, wound repair was examined in
MIP-1-/- and MCP-1-/- mice.
Surprisingly, wound re-epithelialization,
angiogenesis, and collagen synthesis in
MIP-1-/- mice was nearly identical to wild-type
controls. In contrast, MCP-1-/- mice displayed
significantly delayed wound re-epithelialization, with the
greatest delay at day 3 after injury (28 ± 5%
versus 79 ± 14% re-epithelialization,
P < 0.005). Wound angiogenesis was also delayed in
MCP-1-/- mice, with a 48% reduction in capillary
density at day 5 after injury. Collagen synthesis was impeded as
well, with the wounds of MCP-1-/- mice containing
significantly less hydroxyproline than those of control mice (25
± 3 versus 50 ± 8 µg/wound at day 5,
P < 0.0001). No change in the number of wound
macrophages was observed in MCP-1-/- mice,
suggesting that monocyte recruitment into wounds is independent of this
chemokine. The data suggest that MCP-1 plays a critical role in healing
wounds, most likely by influencing the effector state of
macrophages and other cell types.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1).
MCP-1 mediates the recruitment of monocytes in several inflammation
models and diseases.1,2
The absence of MCP-1 leads to
attenuated monocyte influx in thioglycolate-induced peritonitis and in
delayed-type hypersensitivity response.3
Mice lacking the
MCP-1 receptor, CCR2, cannot recruit macrophages to the inflamed
peritoneum,4
are not able to clear Listeria
monocytogenes infection,5
or to develop
granulomas.6
MCP-1 is abundant in atherosclerotic lesions,
leading to the postulation that MCP-1 and other chemokines, such as
MIP-1, may be involved in monocyte recruitment and the subsequent
development of these lesions.7
Similar to MCP-1, MIP-1 can mediate the recruitment
of monocytes in several inflammatory diseases.8-12
MIP-1 also leads to a local accumulation of neutrophils when it is
subcutaneously injected.13,14
MIP-1 has been shown to
play a role in several inflammatory diseases. For example,
bleomycin-induced pulmonary fibrosis is decreased when MIP-1 is
inhibited,15
and influenza-induced pneumonitis is
dependent on the presence of MIP-1.16
These many
studies support the notion that both MCP-1 and MIP-1 are key
molecules in macrophage trafficking into inflammatory foci.
A number of studies have demonstrated the expression and function of
chemokines in healing wounds.17-20
Overall, the
expression pattern of chemokines in wounds has been shown to correlate
well with the known sequence of neutrophil, macrophage, and lymphocyte
recruitment in wounds.19
In particular, studies in our own
laboratory have demonstrated that both MCP-1 and MIP-1 are expressed
in high levels in murine full-thickness dermal wounds at time points
preceding and coincident with maximal macrophage
infiltration.21,22
Taken together, these and other studies
have established a role for chemokines in wound inflammation.
The generation of the MIP-1- and MCP-1-deficient mice
(MIP-1-/- and
MCP-1-/-) provided an opportunity to test the
requirement of these chemokines for wound repair in a genetically
defined system. Given the central role of these chemokines in many
different inflammatory responses, as well as their established presence
in early wound healing, we hypothesized that mice deficient in either
MCP-1 or MIP-1 would display altered wound repair. This study
characterizes and compares wound healing in MCP-1 and MIP-1
genetically deficient mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MIP-1-/- (B6.Scya3)16
and
MCP-1-/- (Scya2)3
mice were
generated as previously described. The genetic background of the
MIP-1-/- mice is C57BL/6, and the genetic
background of MCP-1-/- mice is 
93% C57BL/6
and 7% SJL.23
The mice were maintained and bred at
Loyola University Medical Center animal facilities. Control C57BL/6
mice were purchased from Harlan Sprague-Dawley, Inc. (Indianapolis,
IN). For wounding studies, mice were anesthetized by inhalation of
methoxyflurane (Metofane; Schering-Plough Animal Health Corp., Union,
NJ.). Full-thickness excisional wounds of 3 mm in diameter were made on
the shaved dorsum of 6- to 7-week-old mice with a standard biopsy punch
(Acuderm, Inc., Ft. Lauderdale, FL). At various time points after
injury, the mice were euthanized by halothane inhalation (Halocarbon
Laboratories, Riveredge, NJ), and the wound with its surrounding tissue
were removed. Wounds were either flash-frozen in liquid nitrogen for
hydroxyproline analysis or embedded in TBS Tissue Freezing Medium
(Triangle Biomedical Sciences, Durham, NC) for histological analysis.
All samples were stored at -80°C until the time of analysis. Sex-
and age-matched mice were used for all experiments. Animal protocols
used in this study were reviewed and approved by the Loyola University
Institutional Animal Care and Use Committee.
Histology and Immunohistology
Ten-µm sections were prepared from frozen embedded tissues. To visualize general wound morphology, slides were stained with hematoxylin and eosin (Sigma Chemical Company, St. Louis, MO). For immunohistochemical staining, the sections were fixed in acetone for 15 minutes. All incubations and washes were performed at room temperature. After three 5-minute washes in phosphate-buffered saline (PBS), pH 7.4, sections were treated with 0.3% (v/v) H2O2 in methanol to quench endogenous peroxidase. The slides were washed in PBS, and blocked with a 1:10 dilution of normal mouse serum (Harlan Bioproducts for Science, Inc., Indianapolis, IN) in PBS for 30 minutes. To detect endothelial cells, sections were incubated in 1.0 µg/ml of MEC 13.3 primary antibody (anti-CD31; Pharmingen International, San Diego, CA). For the detection of macrophages, 1.7 µg/ml of rat anti-mouse MOMA-2 antibody (Sertotec Inc., Raleigh, NC) was used. This antibody recognizes an intracellular antigen in monocytes and macrophages.24 After a 30-minute incubation with the primary antibody, the slides were washed for 5 minutes, three times, in PBS and incubated with 13.0 µg/ml of biotinylated mouse anti-rat IgG antibody (Jackson Laboratories, West Grove, PA) for another 30 minutes. After three 5-minute washes in PBS, slides were incubated with avidin-biotin-horseradish peroxidase complex (ABC-HRP; Vector Laboratories, Burlingame, CA) for 30 minutes. After the final set of washes, slides were incubated in an HRP substrate, 3,3'-diaminobenzidine (Kirkegaard and Perry Laboratories, Gaithersburg, MD) for 10 minutes and the sections were counterstained with Harris hematoxylin (Sigma Chemical Company, St. Louis, MO). Slides were mounted with Cytoseal (Stephens Scientific, Kalamazoo, MI). To quantify macrophages, wound bed areas were outlined and measured using Scion Image beta 3b acquisition and analysis software (Scion Corp., Frederick, MD). MOMA-2-positive cells were counted within the wound bed, and the number of macrophages per mm2 determined. For each group, two wound sections from each of four individual mice were analyzed. All counting was performed in a blinded manner.
Analysis of Re-Epithelialization
To analyze the degree of re-epithelialization, the central portion
of the wound was viewed under x100 or x400 power. The width of the
wound, and the distance that the epithelium had traversed were
measured. The percent re-epithelialization was calculated with the
following formula:
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Analysis of Angiogenesis
To analyze blood vessel density in wound samples, endothelial
cells were visualized by CD31 immunohistochemistry. Images of
CD31-immunostained wound sections were captured and analyzed using
Scion Image beta 3b acquisition and analysis software (Scion Corp.).
The wound bed was outlined using a freehand drawing tool and the area
was measured. CD31+ area within the wound was
highlighted with false coloring and the intensity and pattern of the
captured image was adjusted to match those of the slide. Background
signals were eliminated either with a picture-editing function in the
program or by setting a higher threshold that includes
CD31+ signals while excluding those from the
hematoxylin counterstain. The CD31-positive area within
the wound bed was measured and the percent vascularization was
calculated as:
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Collagen Analysis
Collagen content of wounds was assessed by determining the amount of hydroxyproline.25 Frozen wound tissue was hydrolyzed in 2.0 ml of 6 N HCl for 3 hours at 130°C or overnight at 110°C. The reaction was neutralized with 2.5 N NaOH and diluted 40-fold with deionized H2O. One ml of a 0.05 mol/L N-chloro-p-toluene-sulfonamide solution was added to 2 ml of the neutralized/diluted solution and incubated for 20 minutes at room temperature. One ml of 3.15 mol/L perchloric acid was added to the solution and was incubated for 5 more minutes at room temperature. One ml of 20% solution of p-dimethylaminobenzaldehyde was then added and the resulting mixture was incubated for 20 minutes at 60°C. The samples were cooled with cold tap water. Absorbance was measured at 557 nm, and the amount of hydroxyproline determined by comparison to a standard curve. All reagents in this assay were purchased from Sigma Chemical Company.
Statistical Analysis
Data were analyzed using GraphPad Prism, version 2.01 (GraphPad Software Inc, San Diego, CA). The means and SEM were calculated for each data set. For the comparison of two groups, an unpaired t-test was used. For data from time-course experiments, a two-way analysis of variance was used. This method determines if there are significant variations in the healing response as a result of genetic strain and/or time. For both tests, significance was taken as P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- Mice
We first examined the degree of re-epithelialization in wounds
from MCP-1-/-,
MIP-1-/- and control mice at 3 days after
injury. This time point was previously characterized as the mid-point
of re-epithelialization in this model.26
At 3 days after
injury, wounds from MCP-1-/- mice showed a
significant delay in re-epithelialization (28 ± 6%
re-epithelialization versus 79 ± 14% in controls,
P < 0.005; Table 1
and
Figure 1
). Although day 5 wounds from
control mice were primarily re-epithelialized, those from
MCP-1-/- mice were still incomplete (Figure 1)
.
In contrast to the delay in wound closure seen in the
MCP-1-/- mice, re-epithelialization of wounds
in MIP-1-/- mice was similar to wild-type
control (70 ± 27%, MIP-1-/-
versus 80 ± 2%, control, on day 3 after injury, not
significant; Table 1
and Figure 1
).
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-/- Mice
To confirm that MIP-1-/- mice heal
normally, we examined two additional aspects of wound healing in this
strain. Wound angiogenesis, assessed as vascular density, was
comparable for MIP-1-/- and control
wild-type mice at all time points examined (Figure 2)
. Wound collagen content, as measured
by the level of hydroxyproline, was nearly identical in
MIP-1-/- and control mice (Figure 2)
.
Analysis of healing in larger excisional wounds (8-mm diameter)
unveiled no significant differences in healing between
MIP-1-/- and control mice (data not
shown). Taken together, the data reinforce the concept that wound
healing proceeds normally in MIP-1-/- mice.
|
The delay in wound healing that had been detected in the
MCP-1-/- mice was examined in further detail.
Time course analysis of re-epithelialization revealed a profound delay
in epithelial regrowth in the MCP-1-/- strain.
When compared to wild-type, MCP-1-/- mice
displayed a significant delay in wound re-epithelialization on days 1,
3, and 5 after injury (Figure 3)
. The
wounds of MCP-1-/- mice ultimately reached
closure at day 10, taking approximately twice as long as those of
control animals to achieve complete re-epithelialization. A time course
analysis of angiogenesis established that the vascular density of
wounds from MCP-1-/- mice was also
significantly decreased from control (Figure 3)
. This decrease in
vascularity was most pronounced on day 5 after injury and differences
from wild-type disappeared by day 10 after injury. The influence of
MCP-1 deficiency on the level of wound hydroxyproline, an indirect
measure of collagen, was also determined (Figure 3)
. When compared to
wounds from control mice, a significant retardation in collagen
production was observed in wounds of MCP-1-/-
mice. The greatest delay occurred on day 5 after injury. By day 10, the
hydroxyproline level in MCP-1-/- mice reached a
level similar to that of wild-type controls.
|
-/- Mice
The number of macrophages in the wound increases during healing
because of their local recruitment from peripheral blood. Both MCP-1
and MIP-1 chemokines may participate in this process as chemotactic
factors. The number of macrophages in day 3 after injury wounds was not
significantly different between MCP-1-/- mice,
MIP-1-/- mice, and wild-type controls (Table 2)
. Enumeration of wound macrophages with
an antibody specific for mature macrophages, F4/80,27
yielded similar results to those obtained using the MOMA-2 antibody
(data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and MCP-1 are found in high levels in the early phase of wound
repair.18-22
The presence of these two chemokines
precedes and coincides with maximal macrophage infiltration, suggesting
that they may mediate the recruitment of these inflammatory cells. The
availability of genetically deficient mice allowed for an assessment of
the role of MIP-1 and MCP-1 on wound healing in a defined system. In
MIP-1-/- mice, examination of the degree of
epithelial growth, wound angiogenesis, and collagen synthesis,
demonstrated no significant delay in repair when compared to control.
Given that MIP-1 is actively transcribed in early wounds, and that
MIP-1 protein is abundant during the inflammatory phase of wound
repair, the lack of an observable phenotype in the MIP-1 genetically
deficient strain is a most surprising finding.22
The data
seem to suggest that MIP-1 production is inconsequential in normal
wounds. A second possibility is that compensatory activity is generated
in the MIP-1-/- mice. In these mice, the
chemokine system may have accommodated to MIP-1 deficiency during
development. The large degree of permissive binding between chemokines
and their receptors suggests that chemokine compensation might easily
occur. MIP-1 is known to be a ligand for CCR1, CCR5, and
CCR9,28,29
yet these three receptors bind to several
chemokines other than MIP-1. For example, CCR1 also binds to RANTES
and MCP-3, and the ligands for CCR5 include RANTES and MIP-1ß. CCR9
is a receptor for MCP-1, -2, and -4; MIP-1ß; RANTES; eotaxin; and
HCC-1. At least two pieces of evidence support the concept that
MIP-1-/- mice have developed a compensatory
mechanism that overcomes the loss of this single chemokine. First,
although normal healing is observed in
MIP-1-/- mice, treatment of normal mice with
neutralizing anti-MIP-1 antiserum results in significantly delayed
wound healing.22
Neutralization of MIP-1 by antiserum
seems likely to represent the abrogation of MIP-1 activity in a
situation in which chemokine compensation has not developed. A second
and comparable example of possible compensation for MIP-1 has been
demonstrated in a murine experimental autoimmune encephalomyelitis
model.30
Whereas treatment of normal mice with
neutralizing anti-MIP-1 antiserum inhibits EAE
development,31
MIP-1-/- mice
are fully susceptible to the disease. Both of these examples suggest
that MIP-1-/- mice produce other factors,
perhaps other chemokines, which fully compensate in some
inflammatory circumstances.
In contrast to the normal healing observed in
MIP-1-/- mice,
MCP-1-/- mice did not display overt
compensation, and exhibited an observable delay in multiple parameters
of healing. In these mice, re-epithelialization, angiogenesis, and
collagen production were remarkably decreased. Although delays were
apparent and often dramatic in the early phases of repair, by day 10
the differences were no longer significant, and the values of the
wounds from MCP-1-/- mice were similar to those
of control animals. Thus, although there is a delay during the healing
process, the ultimate endpoints are similar in wounds from both
knockout and control animals. The transient but significant nature of
the delay is very similar to those observed in wounds from mice
deficient in basic fibroblast growth factor32
and in
wounds of aged mice.26
Although there is a delay in the repair process, no reduction in macrophages, as identified by MOMA-2 antibody, was seen in wounds of the MCP-1-/- mouse. Because MOMA-2 detects nearly all monocytes and macrophages, without distinction as to activation status, the possibility exists that specific subsets of macrophages, such as activated populations, are decreased in the MCP-1-/- mice. The finding of normal levels of macrophages in MCP-1-/- mice, in the face of altered healing, is consistent with the notion that it is not only the presence, but also the appropriate activity of these cells that is important for proper progression of wound healing.33-35 As macrophages are a rich source of growth factors, the absence of MCP-1 may have affected the ability of these cells to produce or secrete the necessary factors. Additional studies to investigate shifts in wound macrophage activity in the MCP-1-/- mice are needed to substantiate this notion.
Our observation of normal inflammatory cell infiltration in the dermal healing model is somewhat different from those from other inflammatory models. MCP-1-/-3 and CCR2-/-4-6 mice had impaired peritoneal inflammation elicited by thioglycolate because of a lack of monocytes/macrophages in the peritoneum. In the autoimmune-prone MRL-faslpr mice that lack MCP-1, the disease was not manifested, because there was a reduction of autoimmune cell invasion.36 The MCP-1-/- leukocytes did not exhibit any delay in proliferation when stimulated in vitro, suggesting that alterations in chemotaxis itself, rather than intrinsic cellular defects were responsible. In mouse models of atherosclerosis,23,37,38 the lack of MCP-1 led to a reduction in macrophage infiltration, and consequently, a decrease in plaque formation. These varied observations suggest a differential requirement for MCP-1 in each particular inflammatory disease environment. MCP-1-/- mice exhibited differential deficits in the various parameters of wound repair, suggesting specific roles for this chemokine. First, our results support the hypothesis that the role of MCP-1 in wounds involves macrophage activation but not recruitment. Second, in regard to the proliferative aspects of wound healing, MCP-1 seems to have greater role in the promotion of epithelial and vascular growth than in the induction of collagen synthesis. Interestingly, among these three proliferative parameters, collagen synthesis showed the least amount of delay in the MCP-1-/- mice. Therefore, within wounds, the role of MCP-1 seems compartmentalized to specific regenerative processes.
A growing body of literature supports the concept that interconnections
exist among the chemokine, cytokine, and growth factor networks. MCP-1
is known to influence macrophage activity, and can also stimulate both
fibroblasts39,40
and endothelial cells.41
Each of these three cell types is known to produce growth factors and
other cytokines within wounds.42
These studies suggest the
possibility that impaired wound healing, such as that observed in aged
or diabetic patients, may involve perturbations in the chemokine
network. An argument for such chemokine dysregulation is supported by a
recent study of patients with chronic nonhealing venous leg ulcers.
Compared to healing wounds, chronic wounds from these patients
exhibited altered chemokine and inflammatory cytokine
profiles.43
In a more specific example of cytokine
interaction in wounds, interleukin-10 has been shown to exert a
regulatory role via inhibition of the expression of MIP-1 and MCP-1,
leading to a diminished wound inflammatory response.44
Additional investigations will be needed to assess the importance of
chemokine, cytokine, and growth factor alterations to the problem of
impaired wound healing.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grants AI 44861–01 (to D. G. Q.), GM 55344 and AG 16067 (to E. J. K.), GM 55238 and GM 50875 (to L. A. D.).
Accepted for publication May 7, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 G. L. Warren, L. O'Farrell, M. Summan, T. Hulderman, D. Mishra, M. I. Luster, W. A. Kuziel, and P. P. Simeonova Role of CC chemokines in skeletal muscle functional restoration after injury Am J Physiol Cell Physiol, May 1, 2004; 286(5): C1031 - C1036. [Abstract] [Full Text] [PDF]
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R. Mori, T. Kondo, T. Nishie, T. Ohshima, and M. Asano Impairment of Skin Wound Healing in {beta}-1,4-Galactosyltransferase-Deficient Mice with Reduced Leukocyte Recruitment Am. J. Pathol., April 1, 2004; 164(4): 1303 - 1314. [Abstract] [Full Text] [PDF]
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H. Amano, K. Morimoto, M. Senba, H. Wang, Y. Ishida, A. Kumatori, H. Yoshimine, K. Oishi, N. Mukaida, and T. Nagatake Essential Contribution of Monocyte Chemoattractant Protein-1/C-C Chemokine Ligand-2 to Resolution and Repair Processes in Acute Bacterial Pneumonia J. Immunol., January 1, 2004; 172(1): 398 - 409. [Abstract] [Full Text] [PDF]
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A. W. M. Minto, L.-P. Erwig, and A. J. Rees Heterogeneity of Macrophage Activation in Anti-Thy-1.1 Nephritis Am. J. Pathol., November 1, 2003; 163(5): 2033 - 2041. [Abstract] [Full Text] [PDF]
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M. L. Lindsey, J. Yoshioka, C. MacGillivray, S. Muangman, J. Gannon, A. Verghese, M. Aikawa, P. Libby, S. M. Krane, and R. T. Lee Effect of a Cleavage-Resistant Collagen Mutation on Left Ventricular Remodeling |
