The Journal of Immunology, 2001, 167: 5316-5320.
Copyright © 2001 by The American Association of Immunologists
IL-1 Plays a Critical Role in Oral, But Not Dermal, Wound Healing
Dana T. Graves1,*,
Nasser Nooh
,
Thomas Gillen
,
Michael Davey*,
Shilpa Patel*,
David Cottrell
and
Salomon Amar*
Departments of
*
Periodontology and Oral Biology,
Oral and Maxillofacial Surgery, and
Endodontics, Boston University School of Dental Medicine, Boston, MA 02118; and
College of Dentistry, King Saud University, Riyadh, Saudi Arabia
 |
Abstract
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Wound healing is a well-orchestrated complex process leading to the
repair of injured tissues. After injury, proinflammatory cytokines act
as important modulators of the inflammatory process. IL-1 expression
has been regarded as necessary for healing; however, its effects have
also been implicated in delayed wound repair. Currently, there is no
consensus or direct evidence that IL-1 activity plays a central role in
the healing process. The present investigation was undertaken to define
the role of IL-1R signaling in the healing outcome of an excisional
wound in the palate or scalp of mice that had targeted deletions of the
IL-1R type 1 (IL-1R1-/-) compared with matched wild-type
mice. Histomorphometric analysis was undertaken to assess the degree of
healing and the recruitment of polymorphonuclear and mononuclear
phagocytes. After 14 days, wild-type mice exhibited complete closure of
intraoral wounds, while IL-1R1-/- animals had only
partial closure (50%). In the IL-1R1-/- mice, healing
tissues exhibited a persistent inflammatory cell infiltrate, which did
not occur in wild-type animals. Treatment with antibiotics
significantly diminished the persistent inflammatory infiltrate and
improved healing in the experimental animals. In contrast to oral
wounds, the rate of healing and recruitment of polymorphonuclear cells
in scalp wounds was similar in IL-1R1-/- and wild-type
mice. The present data underscore the importance of IL-1 in wound
healing in a challenging environment and identify its principal role in
facilitating the healing process by protecting an open wound from
bacterial insult. In a less challenging environment, the production of
new connective tissue and its coverage by migrating epithelium are
minimally affected by the absence of IL-1
activity.
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Introduction
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Wound healing
has three principal phases (1). Healing is initiated by an
inflammatory phase in which cytokines and other inflammatory mediators
are generated. This is followed by a proliferation phase, particularly
of fibroblasts and endothelial cells. The last phase involves the
production and reorganization of extracellular matrix leading to repair
or regeneration. The inflammatory phase is thought to be important in
the repair process because it leads to the recruitment of leukocytes
that produce growth factors and remove the debris of the wound. A
number of inflammatory mediators are up-regulated during the healing
process, including IL-1. Surprisingly, there is little direct evidence
establishing whether this up-regulation is functionally important.
However, mice with targeted deletion of both P- and E-selectins exhibit
reduced recruitment of inflammatory cells (neutrophils and macrophages)
and impaired closure of the wounds, demonstrating the functional
importance of inflammatory events (2). This is consistent
with earlier studies demonstrating impaired healing in animals depleted
of monocytes (3). Thus, expression of inflammatory
cytokines, including IL-1, may play a central role in the early events
of wound healing, in part because they stimulate the recruitment of
leukocytes.
IL-1 is a potent proinflammatory cytokine that regulates many aspects
of the immune response (4). There are two IL-1 ligands
with agonist activity, IL-1
and IL-1
. Both bind to IL-1Rs termed
type I and type II. The type I IL-1R (IL-1R1) is responsible for
specific signaling, while the type II receptor functions as a
nonsignaling decoy receptor. The generation of mice with targeted
functional deletions of IL-1R1 (IL-1R1-/-) has
helped elucidate the role of IL-1R signaling in several processes
(5, 6). These mice develop normally, do not exhibit gross
abnormalities, and are capable of developing Abs to exogenous Ag
stimulation. In most, but not all studies, mice with deficient IL-1
activity exhibit an attenuated inflammatory response as measured in the
turpentine abscess formation model, and are often more susceptible to
infectious agents (6, 7, 8).
In healing tissue, IL-1 is produced primarily by cells of the
epithelium, and exogenous IL-1 has been shown to accelerate epidermal
healing (9, 10). However, findings that IL-1 is
overexpressed in wounds that heal poorly have cast doubt on the
positive role of IL-1 in the healing process (11, 12).
Further evidence indicates that application of exogenous IL-1R
antagonist can partially reverse the negative impact of TNF on healing
(13). That wound healing is enhanced in mice that have a
lower level of cytokine expression compared with normals also suggests
that the expression of cytokines may inhibit repair even under normal
conditions (14). Thus, there are reports indicating that
proinflammatory cytokines such as IL-1 are expressed during wound
healing, but it is not known whether IL-1 ultimately is required for
normal repair.
In this work, we present studies examining the impact of IL-1 activity
on wound repair by studying the healing response in mice with targeted
mutation of the IL-1R1 and matched wild-type counterparts. These
studies were conducted by placing small excisional biopsies at two
different sites, the scalp and the hard palate. In the latter, a
relatively significant commensal flora is present. The results indicate
that the capacity to recruit polymorphonuclear cells
(PMNs)2 and monocytes
under normal conditions was not dependent upon IL-1. However, for oral
wounds in the IL-1R-deficient mice, there was a failure to reduce the
inflammatory infiltrate at later time points, diminished formation of
new connective tissue, and delayed covering of the wound by epithelium.
Treatment with antibiotics reversed these deficits to a significant
extent. In contrast, healing in the scalp was minimally affected by the
absence of IL-1R signaling. Thus, IL-1R signaling is critical for
normal wound healing in a challenging environment, which is largely due
to its essential function in up-regulating antibacterial defenses. In
contrast, the absence of IL-1R signaling in a less challenging
environment has only a small effect on the wound healing response. To
our knowledge, the present study is the first to address the
mechanistic role of IL-1 signaling in wound healing.
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Materials and Methods
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Mice
Experimental IL-1R1-/- mice on a
C57BL/6 x 129 background and control C57BL/6 x 129
F2 wild-type mice were purchased from The Jackson
Laboratory (Bar Harbor, ME). For all data points, six animals were
examined. For all procedures, mice were anesthetized with injection of
ketamine (80 mg/kg) and xylazine (10 mg/kg) in sterile PBS. A 1.5-mm
palatal excisional biopsy was placed anterior to the soft palate, or a
1.5-mm excisional scalp biopsy was placed at a midline between the ears
after the area was carefully shaved. Animals received either a palatal
or scalp biopsy, but not both. In some experiments, mice were given the
antibiotics sulfamethoxazole (8 mg/ml) and trimethoprim (1.6 mg/ml) in
their drinking water starting 10 days before excisional wounding and
continuing thereafter. Water with fresh antibiotics was changed daily.
Mice were sacrificed at the indicated time points by
CO2 overdose.
Preparation of specimens
Following sacrifice, the head of each animal was dissected free
and then placed for 48 h in cold 4% paraformaldehyde, followed by
dissection of the calvaria with intact soft tissue. This tissue was
decalcified by incubation in cold Immunocal (Decal, Congers, NY) for
approximately 4 days, with solution changed daily. Cryostat sections (5
µm) were then prepared as previously described (15).
Quantitative histologic analysis
The distance between the edges of the epithelium and connective
tissue of the wound was measured with the use of Image ProPlus software
(Media Cybernetics, Silver Spring, MD) from sections at the central
portion of each wound. The number of PMNs was identified by their
characteristic morphology in H&E-stained sections and counted at x1000
magnification. The presence of mononuclear phagocytes was determined by
immunohistochemistry using the F4/80 Ab, as we have previously
described (16). Blood vessels were identified with the
MECA-32 Ab, which recognizes newly formed blood vessels
(17), purchased from BD Biosciences (Franklin Lakes, NJ).
Measurements of mononuclear phagocytes, PMNs, and blood vessels were
made in the healing connective tissue and expressed as the number per
connective tissue area. All quantitative measurements were confirmed by
random reanalysis of approximately one-fourth of the specimens by the
same examiner and by another independent examiner to ensure
consistency. The intra- and interexaminer variation was generally
<15%; each data point presented represents the mean of six
specimens ± SEM. In experiments with multiple time points,
differences between the experimental and the wild-type groups were
determined by ANOVA with significance set at the 0.05 level. Student’s
t test was used to establish differences between
experimental and wild-type groups in other experiments.
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Results
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Following placement of a 1.5-mm excisional wound in the hard
palate, healing was significantly delayed in the IL-1R-deficient mice,
as measured by the gap between the edges of the healing connective
tissue as well as the gap between the healing epithelium (Fig. 1
). Significantly less closure of the
wound by connective tissue or epithelium was observed in the
IL-1R-ablated mice compared with the wild-type animals at days 4, 7,
and 14 (Fig. 2). By day 4 in the
wild-type mice, new connective tissue had covered approximately 40% of
the original wound surface, and new epithelium approximately 50%. A
similar degree of healing was not seen until day 14 in the
IL-1R1-/- animals. In contrast, there was
complete bridging of the wound by both connective tissue and epithelium
in the wild-type animals by day 14.
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FIGURE 1. Healing of excisional oral wounds is delayed in IL-1R-/-
mice. A 1.5-mm palatal excisional wound was placed in the hard palate
of experimental and matched wild-type mice. Animals were sacrificed 7
days later. Specimens were prepared for cryostat sectioning and stained
with H&E. The gap between the healing connective tissue is denoted by
long arrows; the interepithelial gap is marked by short arrows.
Original magnification, x40.
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FIGURE 2. Healing of excisional oral wounds is delayed in IL-1R-/-
mice. A 1.5-mm palatal excisional wound was placed in the hard palate
of experimental and matched wild-type mice. Animals were sacrificed 0,
2, 4, 7, and 14 days following biopsy. The gap between the healing
connective tissue and epithelium was calculated by image analysis of
H&E-stained sections at the wildest part of each lesion. Differences
between experimental and control groups were significant at days 4, 7,
and 14 (p < 0.05).
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In Fig. 3, the data were stratified so
that the animals were placed into one of three groups: 1) those that
showed a high degree of connective tissue healing (covering >70% of
the original wound surface), 2) moderate (covering 30–70%), or 3)
little to no healing (covering <30%). For the wild-type group, the
majority of animals exhibited moderate healing by day 4, whereas none
of the IL-1R1-/- mice exhibited this degree of
healing at the same time point. On day 14, all of the wild-type mice
had a high degree of healing, while two-thirds of the
IL-1R1-/- mice had only a moderate degree of
healing. Taken together, these data indicate that from day 4 onward the
majority of experimental mice exhibited delayed healing compared with
wild-type controls.
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FIGURE 3. A high percentage of excisional oral wounds in
IL-1R-/- mice exhibits delayed healing. Mice described in
Fig. 2 were stratified into three groups: 1) those that showed a high
degree of connective tissue healing (covering >70% of the original
wound surface), dark bars; 2) moderate (covering 30–70%), gray bars;
or 3) little to no healing (covering <30%), light bars. Clear
differences between the experimental and control groups are noted on
days 4, 7, and 14.
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Since angiogenesis is an important component of healing, we determined
whether the formation of new blood vessels was hindered by the absence
of IL-1R signaling by quantitative immunohistochemistry using an Ab
that recognizes newly formed blood vessels, MECA-32. The results
indicate that there were 90 ± 18 blood vessels per
mm2 in the wild-type and 76 ± 12 in the
IL-1R-/- group (mean ± SD). The
difference was not statistically significant (p
> 0.05), suggesting that other mechanisms are responsible for the
differences in the rates of wound repair.
Since IL-1 stimulates many of the cellular events that lead to
formation of an inflammatory infiltrate, experiments were undertaken to
determine whether IL-1R1-/- mice had a
diminished capacity to recruit monocytes and neutrophils (Fig. 4). In these experiments, monocytes and
PMNs were counted in the healing connective tissue of the wound.
Monocytes were detected by quantitative immunohistochemistry, as
CD68-positive cells and neutrophils were identified by their
characteristic appearance on H&E-stained sections. On day 2, enhanced
recruitment of both monocytes and PMNs was observed in all of the
animals tested compared with baseline. Unexpectedly, the number of
monocytes present following wounding was higher in the experimental
animals compared with controls. In this group, large numbers of
monocytes were recruited by day 2 and did not decrease thereafter. In
contrast, the number of monocytes in wild-type mice peaked at day 4 and
decreased to almost normal levels by day 14. PMNs in the wild-type
group also peaked on day 4 and returned to baseline levels by day 14.
In contrast, the recruitment of PMNs in IL-1R-ablated mice reached high
levels by day 2 that persisted for the entire experimental period.
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FIGURE 4. Healing oral wounds in IL-1R1-/- mice have a persistent
monocyte and PMN infiltrate. Histologic sections were analyzed for the
presence of mononuclear phagocytes or PMNs in the connective tissue of
the healing wound. Mononuclear phagocytes were identified by
immunohistochemistry using an Ab to CD68 and PMNs by their
characteristic appearance in H&E sections.
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We previously reported that IL-1R1-/- mice
exhibited a limited capacity to resist infection by oral pathogens
(18). We therefore tested whether the delayed oral healing
observed in the IL-1R1-/- animals was due to a
limited capacity to protect the wound site from infection. In these
experiments, mice were treated with an antibiotic regimen that has been
reported to substantially reduce the commensal flora in the oral cavity
of mice (19). Before antibiotic treatment, high bacterial
counts were obtained from a swab of the hard palate of both the
experimental and control mice (Fig. 5).
Just before creation of an excisional wound, the bacterial flora was
reduced by >1000-fold, and 1 wk after biopsy, during the period of
healing, only a few bacterial colonies were detected.
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FIGURE 5. Antibiotic treatment reduces bacterial levels in the palates of
IL-1R-/- and wild-type mice. One group of mice was
treated with antibiotics, sulfamethoxazole (8 mg/ml), and trimethoprim
(1.6 mg/ml) in their drinking water starting 10 days before inducing an
oral excisional wound and continuing thereafter. Swabs of the palate
were cultured under aerobic conditions to assess bacterial colony
formation just before antibiotic treatment, at the time of surgery, and
7 and 14 days after wounding.
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The effect of antibiotic treatment was assessed by histomorphometric
analysis of H&E-stained sections from mice sacrificed on day 14, which
was selected because the greatest difference in healing was noted
between the experimental and control groups at this time point (see
Fig. 1). Experimental mice treated with antibiotics had a significantly
improved healing response (Fig. 6).
Epithelial and connective tissue wound closure was improved by 50% and
65%, respectively, in the antibiotic-treated group of
IL-R-/- animals. In the wild-type animals,
healing was completed at this time point with or without antibiotics
(data not shown).
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FIGURE 6. Antibiotic treatment enhances the rate of healing in
IL-1R-/- mice. An excisional wound was placed in the
palate of IL-1R1-/- mice, which were sacrificed 14 days
later. In one group, mice were treated with antibiotics, as described
in Fig. 6. Histologic measurements of the connective tissue and
epithelial gaps were made from H&E-stained sections. The differences
between the treated and untreated groups for the
IL-1R1-/- mice were significant (p <
0.05).
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To measure the impact of antibiotic treatment on formation of an
inflammatory infiltrate, the number of PMNs was counted. When the
IL-1R-/- group was treated with antibiotics,
there was a 63% reduction in the number of PMNs so that the level was
similar to that in the untreated wild-type mice (Fig. 7). This indicates that much of the
prolonged recruitment of PMNs in the experimental group is due to
constant bacterial stimulation. Moreover, it is consistent with a
subclinical infection since no overt signs of infection were present at
the wound site.
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FIGURE 7. Antibiotic treatment reduces the size of the inflammatory infiltrate
following wounding in IL-1R1-/- mice. Mice were treated
with antibiotics, as described in Fig. 6. An excisional biopsy was
placed in the palate, and animals were sacrificed 14 days later. PMNs
were counted at x1000 magnification in the healing connective tissue
in H&E-stained sections. The difference between treated and nontreated
groups was significant for IL-1R1-/- animals
(p < 0.05).
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Experiments were then undertaken to examine healing in experimental and
wild-type animals under conditions in which bacterial challenge was
less significant. To accomplish this, a 1.5-mm excisional wound was
created in the scalp and the rate of healing determined (Fig. 8). At this site, the rates of healing in
the wild-type and control mice were similar, except for a single time
point, day 7. This contrasts sharply with different rates of healing
observed in the oral cavity. When the data were stratified into groups
consisting of a high degree, moderate, or little healing, the
distribution was similar for wild-type and
IL-1R1-/- mice, also indicating that the rates
of healing between the two groups were similar (data not shown).
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FIGURE 8. Healing of excisional wounds in the scalp is similar in
IL-1R-/- and wild-type mice. A 1.5-mm biopsy was placed
in the scalp of experimental and control mice at a point midway between
the ears. Animals were sacrificed 0, 2, 4, 7, and 14 days later.
Histologic measurements of the connective tissue and epithelial gaps
were made from H&E-stained sections at the widest point of each lesion.
A significant difference between experimental and control groups was
observed only on day 7 (p < 0.05).
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The impact of IL-1R signaling on formation of an inflammatory
infiltrate following wounding in the scalp was determined by measuring
the number of PMNs (Fig. 9). In the
wild-type and IL-1R1-/- groups, there was a
significant increase in the number of PMNs on day 2. For both groups,
the size of the inflammatory infiltrate decreased considerably by day
7, although they were still above baseline levels. No significant
differences were noted between IL-1R-deficient and wild-type mice at
any of the time points.
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FIGURE 9. Recruitment of PMNs is similar in IL-1R-/- and wild-type
mice in excisional wounds of the scalp. A 1.5-mm biopsy was placed in
the scalp, as described in Fig. 7. PMNs were counted in H&E-stained
sections at x1000 magnification in the healing connective tissue.
Differences between the IL-1R1-/- mice and wild-type mice
were not significant (p > 0.05).
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Discussion
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It has been documented in several reports that IL-1 is
up-regulated during wound healing. However, there is no consensus or
direct evidence that IL-1 activity plays a central role in the healing
process. Thus, the significance of its expression is poorly understood.
The present study addresses this issue and demonstrates that in a
challenging environment the loss of IL-1R signaling causes a
significant delay in excisional wound healing. In contrast, healing in
the scalp is minimally affected by ablation of IL-1Rs. The difference
between these two outcomes can be reconciled by the fact that a
significant reduction in the oral flora greatly enhances the rate of
healing in IL-1R1-/- mice. These data
underscore the role of IL-1 in wound healing and identify its principal
role in facilitating the healing process by protecting an open wound
from bacterial insult.
In oral healing, monocyte and PMN infiltration was significantly
reduced by day 7 in the wild-type animals, while it was maintained
without a reduction in the experimental mice. Experiments in which mice
were treated with antibiotics suggest that persistent bacterial
challenge in the oral cavity of IL-1R1-/- mice
may account for the long period of inflammation and duration of
the inflammatory infiltrate. This is likely to result from an
impairment of the host response in the experimental group, since IL-1
has been shown to significantly contribute to the antibacterial
activity of PMNs and monocytes (20, 21, 22). This
interpretation is consistent with our previous finding that in a model
of chronic infection, IL-1R1-/- mice had an
impaired antibacterial defense, as demonstrated by higher levels of
oral pathogens at infected sites compared with wild-type animals
(16), which was associated with prolonged recruitment of
leukocytes. Thus, a diminished host response present in the
IL-1R1-/- mice could lead to a mild subclinical
infection at the wound site, inducing persistent inflammation, and that
in turn causes impaired healing. These results may give insight into
mechanisms of delayed wound healing in which there is a compromised
host response in individuals such as diabetics (23).
Results from excisional wounds in the scalp demonstrate that ablation
of IL-1Rs has only a small effect on formation of new connective tissue
and wound coverage by epithelium. This further emphasizes that the
deficit in oral healing is due to the impact of that particular
environment rather than an absolute requirement for IL-1 stimulation of
fibroblasts or epithelial cells. It is also consistent with studies
demonstrating that reformation of an epithelial barrier following
repeated treatment of the skin with acetone or tape stripping is not
significantly affected by the absence of IL-1Rs (24).
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Footnotes
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1 Address correspondence and reprint requests to Dr. Dana T. Graves, Division of Oral Biology, Boston University School of Dental Medicine, W-202D, 700 Albany Street, Boston, MA 02118. E-mail address: dgraves{at}bu.edu 
2 Abbreviation used in this paper: PMN, polymorphonuclear cell.
Received for publication June 1, 2001.
Accepted for publication August 28, 2001.
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Mycophenolate Mofetil Inhibits Regenerative Repair in Uranyl Acetate-Induced Acute Renal Failure by Reduced Interstitial Cellular Response
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Abstract
Introduction
