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*
Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; and
Department of Immunology, Duke University Medical Center, Durham, NC 27710
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production was inhibited in each deficient mouse,
which paralleled the reductions in cutaneous inflammation. These
results indicate that ICAM-1 and L-selectin cooperatively contribute to
the cutaneous Arthus reaction by regulating neutrophil and mast cell
recruitment and suggest that ICAM-1 and L-selectin are therapeutic
targets for human IC-mediated disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rs) play a central role in the initiation of IC-triggered
inflammation (3, 4). Specifically, the FcR type III
(FcRIII, CD16) on mast cells initiates the cutaneous Arthus reaction
since mast cell-deficient
Kitw/KitW-v mice and
FcRIII-deficient (FcRIII-/-) mice exhibit
substantially reduced inflammation (5, 6, 7, 8, 9). C5aR expression
is also required for normal neutrophil influx and edema formation
during the cutaneous Arthus reaction (10). Although FcR
and C5aR are codominant receptors in the initiation of a cutaneous
Arthus reaction, few studies have addressed the contribution of
leukocyte accumulation to the effector phase of the reaction.
Leukocyte recruitment into inflammatory sites is achieved using
distinct constitutive or inducible families of cell adhesion molecules
(11, 12, 13). L-selectin (CD62L) which primarily mediates
leukocyte capture and rolling on the endothelium is constitutively
expressed by most leukocytes (14, 15). In vitro,
L-selectin binds several glycosylated mucin-like proteins expressed by
high endothelial venules (15). Cytokine-inducible ligands
for L-selectin have also been described for peripheral endothelial
cells, but their identity remains unknown (16, 17, 18).
L-selectin-/- mice demonstrate decreased
trauma- and TNF--induced rolling of leukocytes, decreased leukocyte
recruitment into an inflamed peritoneum, decreased delayed-type
hypersensitivity responses, delayed rejection of allogeneic skin
transplants, and resistance to LPS -induced septic shock
(19, 20, 21, 22, 23, 24, 25). ICAM-1 (CD54) is constitutively expressed at low
levels by endothelial cells and is rapidly up-regulated during
inflammation, resulting in increased leukocyte-endothelial cell
adhesion (26). Leukocytes express
2 integrins, including LFA-1 (CD11a/CD18),
which interact with ICAM-1. ICAM-1-2 integrin
interactions promote leukocyte rolling, but also mediate firm adhesion
and the transmigration of leukocytes at sites of inflammation
(13, 27). ICAM-1-/- mice have
significantly reduced numbers of infiltrating neutrophils during
peritonitis, reduced susceptibility to LPS-induced septic shock,
delayed skin wound repair, and impaired delayed-type hypersensitivity
reactions, although allogeneic skin graft rejection is normal
(20, 28, 29, 30). Recent studies using
L-selectin/ICAM-1-/- mice demonstrate a direct
role for ICAM-1 in leukocyte rolling as the frequency of rolling
leukocytes in L-selectin-/- mice treated with
TNF- is decreased significantly by the additional loss of ICAM-1
expression (27). Furthermore, the loss of both L-selectin
and ICAM-1 expression reduces leukocyte recruitment into sites of
inflammation beyond what is observed with loss of either receptor alone
(30, 31). Therefore, L-selectin and ICAM-1 mediate optimal
leukocyte accumulation during inflammation through overlapping as well
as synergistic functions.
Neutrophils and mast cells are the primary effector cells in the cutaneous Arthus reaction (1, 7, 8, 32). Despite this, studies investigating the role of adhesion molecules mediating IC-induced neutrophil migration are limited. P-selectin expression is detected along vessel walls before neutrophil accumulation in the rat cutaneous Arthus reaction, with neutrophil accumulation inhibited by mAb against P-selectin (33). Similarly, pretreatment with anti-CD18 mAb inhibits neutrophil influx in the cutaneous Arthus reaction of rat and rabbit (34, 35). Although a critical role for L-selectin and ICAM-1 has been demonstrated in various inflammatory models (27, 30, 31), it is unknown whether L-selectin and ICAM-1 contribute to the cutaneous Arthus reaction by mediating leukocyte recruitment in vivo. For this purpose, we analyzed inflammation induced by IC in mice lacking either L-selectin, ICAM-1, or both receptors. The results demonstrate that ICAM-1 and L-selectin cooperatively contribute to IC-induced skin injury by regulating the accumulation of mast cells and neutrophils.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L-selectin-/- mice were produced as described previously (19). ICAM-1-/- mice (28) expressing residual amounts of ICAM-1 splice variants in the thymus and spleen but not in other organs, including skin (36), were obtained from The Jackson Laboratory (Bar Harbor, ME). Mice lacking both L-selectin and ICAM-1 were generated as described elsewhere (27). All mice were healthy, fertile, and did not display evidence of infection or disease. All mice were backcrossed between 5 and 10 generations onto the C57BL/6 genetic background. Mice used for experiments were 12–16 wk old. Age-matched wild-type littermates and C57BL/6 mice (The Jackson Laboratory) were used as controls with equivalent results so all control results were pooled. All mice were housed in a specific pathogen-free barrier facility and screened regularly for pathogens. All studies and procedures were approved by the Committee on Animal Experimentation of Kanazawa University School of Medicine.
Reverse passive Arthus reactions
For cutaneous Arthus reactions, mice anesthetized by inhalation of diethyl ether were shaved on their dorsal skin and wiped with 70% alcohol. Rabbit IgG anti-chicken egg albumin Abs (60 µg/30 µl; Cappel, Aurora, OH) were injected intradermally with a 29-gauge needle, followed immediately thereafter by i.v. injection of chicken egg albumin (20 mg/kg; Sigma-Aldrich, St. Louis, MO) (10). The intradermal injection of purified polyclonal rabbit IgG (60 µg/30 µl; Sigma-Aldrich) followed by i.v. installation of chicken egg albumin served as a control. The solution of chicken egg albumin contained 1% Evans blue dye (Sigma-Aldrich). Tissues were harvested 4 or 8 h later and assessed for edema, hemorrhage, and numbers of infiltrating neutrophils and mast cells.
The peritoneal reverse passive Arthus reaction was initiated by the i.v. injection of chicken egg albumin at 20 mg/kg, followed immediately by the i.p. injection of 800 µg of rabbit IgG anti-chicken egg albumin Ab or control purified rabbit polyclonal IgG in a volume of 400 µl. Four or 8 h later, the peritoneum was exposed by a midline abdominal incision, and 5 ml of ice-cold PBS containing 0.1% BSA was injected into the peritoneal cavity via a 27-gauge needle. Cells in the recovered lavage fluid were centrifuged onto glass slides and stained with Giemsa for light microscopic examination to quantify neutrophil and mast cell numbers.
Quantitation of edema and hemorrhage
Edema was evaluated by two methods 4 h after IC challenge (10). First, the diameter of extravascular Evans blue dye on the reverse side of the injection site was measured directly. Evans blue dye binds to serum proteins and thereby can be used to quantify alterations in vascular permeability. The diameter of the major and minor axis of the blue spot was averaged for analysis. Second, the injection area or a control site was removed using a disposable sterile 6-mm punch biopsy (Maruho, Osaka, Japan), and each tissue section was weighed. The amount of hemorrhage was assessed 8 h after IC challenge by direct macroscopic measurement of the purpuric spot. The diameter of the major and minor axis of the blue spot was averaged for analysis.
Histological examination and immunohistochemical staining
Tissues were fixed in 3.5% paraformaldehyde and then paraffin embedded. Six-micrometer sections were stained using H&E for neutrophil evaluation and toluidine blue for mast cell staining. Extravascular neutrophils and mast cells were counted in the entire section. For immunohistochemistry, tissue sections of skin biopsies were acetone fixed and then incubated with 10% normal rabbit serum in PBS (10 min, 37°C) to block nonspecific staining. Sections were then stained with rat mAbs specific for mouse ICAM-1 (Beckman Coulter, Miami, FL) as described previously (30). Rat IgG (Southern Biotechnology Associates, Birmingham, AL) was used as a control for nonspecific staining. Sections were then incubated sequentially (20 min, 37°C) with biotinylated rabbit anti-rat IgG secondary Abs (Vectastain avidin-biotin complex method; Vector Laboratories, Burlingame, CA), then HRP-conjugated avidin-biotin complexes (Vectastain ABC method; Vector Laboratories). Sections were finally developed with 3,3'-diaminobenzidine tetrahydrochloride and hydrogen peroxide and counterstained with methyl green.
Flow cytometric analysis
After lavage fluid recovery, it was immediately placed on ice to inhibit the endoproteolytic release of cell surface L-selectin. Isolated peritoneal lavage cells (0.5 x 106) were stained using predetermined optimal concentrations of either anti-c-Kit-FITC Ab (CD117, clone 2B8; BD PharMingen, San Diego, CA) or anti-Gr-1-FITC Ab (clone RB6-8C5; BD PharMingen) plus either anti-CD18-PE Ab (clone C71/16; Beckman Coulter) or anti-L-selectin-PE Ab (clone MEL-14; Beckman Coulter) for 20 min at 4°C as described elsewhere (37, 38). Cells were washed and analyzed on a FACScan flow cytometer (BD PharMingen) by gating on c-Kit-positive mast cells or Gr-1-positive granulocytes. Positive and negative populations of cells were determined using unreactive isotype-matched mAbs (Beckman Coulter) as controls for background staining.
RT-PCR and real-time PCR
Total RNA was isolated from frozen skin tissues using a RNA PCR
kit according to the manufacturer’s instructions (Promega, Madison,
WI). RNA yield and purity were determined by spectrophotometry. RNA was
then reverse transcribed into cDNA and amplified. Amplification was
performed in a PCR thermal cycler MP (Takara, Kusatsu, Japan) for 30
cycles of denaturation at 94°C for 30 s, annealing at 60°C for
45 s, and extension at 72°C for 60 s. The final extension
was performed for 10 min and then for 5 min at 5°C. The sense primer
for mouse TNF- was 5'-AGC CCA CGT AGC AAA CCA CCA A-3' and the
antisense primer was 5'-ACA CCC ATT CCC TTC ACA GAG CAA T-3' (Bex,
Tokyo, Japan). The sense primer for -actin was 5'-GTG GGG CGC CCC
AGG CAC CA-3' and the antisense primer was 5'-GCT CGG CCG TGG TGG TGA
AGC-3' (Bex). The PCR products were electrophoresed on a 2% agarose
gel and stained with ethidium bromide.
Real-time PCR was performed as previously described (39).
Briefly, RNA was isolated and reverse transcribed as described above.
The level of TNF- mRNA was determined by real-time PCR using the
predeveloped TaqMan probe and primers to TNF- (Applied Biosystems,
Foster City, CA) on a model 7700 Applied Biosystems Prism Sequence
Detector (Applied Biosystems). The 18S rRNA endogenous control (Applied
Biosystems) was used to normalize RNA. The TNF- mRNA level in
wild-type littermates was used as the calibrator. Real-time RT-PCR
assays were conducted in triplicate for each sample.
Statistical analysis
The Mann-Whitney U test was used for determining the level of significance of differences in sample means and Bonferroni’s test was used for multiple comparisons.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cutaneous inflammation induced by an Arthus reaction can be
separated into two distinct responses: edema, which reaches a maximum
at 3–4 h after IC challenge, and hemorrhage, which peaks in intensity
at 8 h (3). Therefore, edema and hemorrhage were
evaluated 4 and 8 h after IC challenge, respectively, in
L-selectin-/-,
ICAM-1-/-, and
L-selectin/ICAM-1-/- mice compared with
wild-type littermates. When edema was assessed by measuring the
diameter of Evans blue dye in the extravascular space, edema was
significantly reduced in L-selectin-/- (31%
decrease, p < 0.0001),
ICAM-1-/- (43%, p < 0.0001),
and L-selectin/ICAM-1-/- mice (51%,
p < 0.0001) compared with wild-type littermates (Fig. 1
A).
ICAM-1-/- mice exhibited significant inhibition
of dye vascular leak when compared with
L-selectin-/- mice (p
< 0.01), whereas the loss of both ICAM-1 and L-selectin resulted in a
significant further reduction of dye vascular leak relative to the
L-selectin loss alone (p < 0.001). Similar
results were obtained when edema was evaluated as the wet weight of
skin biopsies from the site of IC formation (Fig. 1B). No
edema was detected in mutant mice or their wild-type littermate
controls following intradermal injection of rabbit polyclonal IgG with
systemic chicken egg albumin (Fig. 1A and data not shown).
Thus, L-selectin loss reduced the early cellular response characterized
by edema, with ICAM-1 deficiency inhibiting edema beyond that found
with L-selectin deficiency.
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C). L-selectin/ICAM-1-/- mice
exhibited significantly reduced hemorrhage compared with both
ICAM-1-/- (p < 0.05)
and L-selectin-/- mice
(p < 0.05). Hemorrhage was not detected in
mutant mice or their wild-type littermate controls following
intradermal injection of rabbit polyclonal IgG with systemic chicken
egg albumin (Fig. 1C and data not shown). Therefore, the
combined loss of L-selectin and ICAM-1 resulted in a greater inhibition
of edema and hemorrhage than the loss of each adhesion molecule
alone. Leukocyte infiltration in the cutaneous Arthus reaction
Extravascular neutrophils were assessed in skin tissue sections
after 4 and 8 h of IC formation (Figs. 2A and 3). Neutrophil numbers
were significantly reduced in
L-selectin-/- (33–34% decrease,
p < 0.05), ICAM-1-/-
(43–54%, p < 0.05), and
L-selectin/ICAM-1-/- mice (54%,
p < 0.005) compared with wild-type mice. The added
loss of L-selectin in ICAM-1-/- mice did not
dramatically affect neutrophil accumulation compared with
ICAM-1-/- mice at either time point. Mast cell
numbers were also assessed in skin tissue sections stained with
toluidine blue (Figs. 2A and
4). Before IC challenge, there were no
significant differences in mast cell numbers between mutant and
wild-type littermates. By contrast, 4 h after IC challenge, mast
cell numbers were significantly reduced in
L-selectin-/- (43% decrease, p
< 0.0001), ICAM-1-/- (52%, p
< 0.0001), and L-selectin/ICAM-1-/- (60%,
p < 0.0001) mice compared with wild-type littermates.
Similar results were obtained after 8 h of IC formation. Mast cell
numbers did not significantly increase in
L-selectin/ICAM-1-/- mice after IC challenge:
the additional loss of ICAM-1 in L-selectin-/-
mice resulted in significantly reduced mast cell numbers relative to
L-selectin-/- mice after both 4 and 8 h
(p < 0.05), while mast cell accumulation was
significantly diminished in
L-selectin/ICAM-1-/- mice compared with
ICAM-1-/-mice (p <
0.01) after 8 h. Thus, the loss of either L-selectin or ICAM-1
expression significantly reduced leukocyte accumulation, but the
combined loss of L-selectin and ICAM-1 led to greater reductions in
leukocyte accumulation than the loss of each molecule alone.
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The i.p. injection of Ab with the i.v. injection of Ag elicits a
reverse passive Arthus reaction characterized by leukocyte influx into
the peritoneal cavity (1). After 4 h of IC challenge,
neutrophil numbers in the peritoneal cavity were significantly reduced
in L-selectin-/- (67% decrease,
p < 0.05), ICAM-1-/- (91%,
p < 0.05), and
L-selectin/ICAM-1-/- mice (67%,
p < 0.01) relative to wild-type littermates (Fig. 2B). After 8 h, neutrophil influx remained
significantly inhibited in both ICAM-1-/-
(67%, p < 0.02) and
L-selectin/ICAM-1-/- mice (53%,
p < 0.01) compared with wild-type littermates. Mast
cell recruitment was also significantly reduced in
L-selectin-/- (42% decrease, p
< 0.01), ICAM-1-/- (64%, p <
0.0001), and L-selectin/ICAM-1-/- mice (68%,
p < 0.0001) after 4 h of IC challenge relative to
wild-type littermates (Fig. 2B). Similar differences were
detected after 8 h. The additional loss of ICAM-1 in
L-selectin-/- mice led to significantly reduced
mast cell numbers compared with L-selectin-/-
mice after 4 and 8 h (p < 0.05). By
contrast, there was no leukocyte influx in mutant mice or their control
littermates following i.p. injection of rabbit polyclonal IgG with
systemic chicken egg albumin (data not shown). Thus, the effect of the
loss of each adhesion molecule on leukocyte recruitment in the
peritoneal Arthus reaction was similar to that observed in the
cutaneous Arthus reaction.
TNF- production
IC stimulate the production and release of TNF- from
infiltrating leukocytes (8, 10, 32, 40), which is detected
1–5 h after the initiation of a peritoneal Arthus reaction but not
after 6 h (40). To assess the involvement of TNF-
in the cutaneous Arthus reaction, TNF- mRNA levels were examined in
the skin after 4 h by RT-PCR (Fig. 5A) and were quantitated by
real-time PCR (Fig. 5B). TNF- mRNA levels were
up-regulated in skin from wild-type and in each adhesion
molecule-deficient mouse after 4 h (Fig. 5A). However,
TNF- mRNA levels were significantly decreased in
L-selectin-/-,
ICAM-1-/-, and
L-selectin/ICAM-1-/- mice relative to their
wild-type littermates (p < 0.0001, Fig. 5B). ICAM-1-/- and
L-selectin/ICAM-1-/- mice exhibited similar
TNF- mRNA levels that were significantly lower than those of
L-selectin-/- mice (p
< 0.001). By contrast, TNF- production was not detected
after 4 h in mice injected with control Ab (Fig. 5A and
data not shown). Thus, reduced cutaneous inflammatory responses in each
adhesion molecule-deficient mouse correlated with reduced TNF- gene
transcription.
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Reduced Arthus reaction-induced mast cell accumulation in adhesion
molecule-deficient mice suggests a role for L-selectin and ICAM-1 in
mast cell recruitment. Therefore, mouse peritoneal mast cells
expressing c-Kit (38, 41) were analyzed for cell
surface L-selectin and/or CD18 (2 integrin)
expression by flow cytometry. Significant L-selectin expression on the
surface of c-Kit-positive mast cells from wild-type mice was
detected when compared with mast cells from
L-selectin-/- mice (Fig. 6A) or staining using an
unreactive isotype-matched control mAb (data not shown). CD18 was also
expressed on mast cells from wild-type mice compared with staining
using an unreactive isotype-matched mAb (Fig. 6A). As a
positive control, granulocytes expressed significant levels of both
L-selectin and CD18 (Fig. 6B). Deficiency of ICAM-1 did not
influence L-selectin or CD18 expression by mast cells or granulocytes
(data not shown). Similarly, the loss of L-selectin did not alter CD18
expression on either of these cell populations (data not shown). Thus,
L-selectin and CD18 were both highly expressed on the surface of mouse
peritoneal mast cells.
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ICAM-1 expression on various types of cells, including
keratinocytes and fibroblasts, is induced by stimulation with
proinflammatory cytokines in vitro (26, 42). Thus, the
loss of ICAM-1 expression on fibroblasts and keratinocytes may
contribute to the reduced inflammation observed in
ICAM-1-/- mice. To assess this, cutaneous
ICAM-1 expression during the Arthus reaction was examined
immunohistochemically. In normal skin, ICAM-1 was detected exclusively
on endothelial cells (Fig. 7A), with up-regulated ICAM-1
expression by endothelial cells 4 h after IC induction (Fig. 7B). However, ICAM-1 expression could not be accurately
assessed on endothelial cells after 8 h since large numbers of
inflammatory cells infiltrating the vessel wall obscured ICAM-1
staining (Fig. 7C). ICAM-1 expression was not detected on
keratinocytes, fibroblasts, or infiltrating inflammatory cells after 4
or 8 h (Fig. 7, B and C, and data not
shown). ICAM-1 expression was not detected in either the intact or
inflamed skin from ICAM-1-/- mice (data not
shown). In addition, the loss of L-selectin expression did not affect
ICAM-1 expression in either the intact or inflamed skin (data not
shown). Thus, ICAM-1 was predominantly expressed on cutaneous
endothelial cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The extent that L-selectin and/or ICAM-1
deficiencies influenced inflammation varied at different time points,
with each cell type, and in different tissues (Figs. 1 and 2). This
suggests that the repertoire of functional adhesion molecules mediating
IC-mediated inflammation changes during the course of inflammation and
is influenced by tissue site. Edema and hemorrhage were generally
inhibited to a larger extent by ICAM-1 deficiency after IC formation
when compared with L-selectin deficiency (Fig. 1). Nonetheless, the
added loss of L-selectin in ICAM-1-/- mice
further diminished inflammatory responses relative to ICAM-1-deficiency
alone (Fig. 1). This is consistent with the finding that L-selectin and
ICAM-1 function cooperatively to mediate optimal leukocyte rolling as
well as to recruit leukocytes into inflammatory sites
(27, 30, 31). In addition to reduced inflammation in
adhesion molecule-deficient mice, neutrophil and mast cell accumulation
in the skin and peritoneum were significantly reduced during Arthus
reactions (
Figs. 2–4). Similarly, reduced cutaneous inflammatory
responses correlated with a significant decrease in TNF- mRNA levels
within skin at sites of IC deposition (Fig. 5). Taken together, these
results demonstrate that ICAM-1 and L-selectin cooperatively contribute
to the development of the cutaneous Arthus reaction by regulating
neutrophil and mast cell accumulation at the inflammatory
site.
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). Thus, reduced Ag-induced
cellular hypersensitivity in L-selectin-/- mice
results from interrupted leukocyte-endothelial cell interactions and
not from reduced immune responses. Furthermore, these results fully
confirm the existence of a peripheral vascular endothelial ligand for
L-selectin.
Mast cells derive from bone marrow progenitors that migrate through the
circulation into tissues where they proliferate and mature
(45). Mature mast cells exist exclusively within tissues,
although mast cell numbers increase at sites of inflammation
(46). Since mature mast cells from the blood accumulate in
the CNS within 1–2 h in response to altered physiological conditions
(47), it is possible that mature mast cells also migrate
from the circulation into inflamed sites. Consistent with this,
peritoneal mast cells expressed significant levels of both L-selectin
and CD18 (Fig. 6). Furthermore, Arthus reaction-induced mast cell
accumulation in both skin and the peritoneum was substantially reduced
in mice lacking L-selectin, ICAM-1, or both adhesion molecules (Fig. 2). It is unlikely that mast cells migrated from surrounding tissues
into sites of inflammation since ICAM-1 expression was only detected on
the endothelium during IC-induced inflammation (Fig. 7), and mast cell
numbers increased rapidly in the peritoneal cavity of wild-type mice
following inflammation (Fig. 2B). Although the exact routes
of mast cell migration into inflamed foci were not determined in this
study, the results suggest that L-selectin and ICAM-1 regulate mast
cell recruitment from the circulation.
Mature peritoneal mast cells expressed CD18 and L-selectin (Fig. 6).
Consistent with this finding, Mac-1 (CD11b/CD18) is expressed by
immature mast cells derived from mouse bone marrow and mature
peritoneal mast cells (41). CD18 expression is also
detected on mast cells in normal human skin, and human mast cell lines
express CD18 (48). With regard to L-selectin expression, a
previous study has shown that immature mast cells derived from mouse
bone marrow do not express L-selectin (49). A second study
has shown that L-selectin is not expressed on mature primary mast cells
isolated from human lung and uterus (50). However, tissue
fragments were first treated with collagenase in the second study and
the isolated mast cells were then cultured for at least 24 h.
L-selectin is rapidly lost from the cell surface of leukocytes
following cellular activation (15). Furthermore,
incubating lymphocytes overnight at 4°C can also result in the
complete loss of L-selectin from the cell surface (51).
Therefore, it is likely that L-selectin expression was
endoproteolytically released from the cell surface during mature mast
cell isolation. Nonetheless, the present study reveals that mature mast
cells freshly isolated from the peritoneal cavity express significant
levels of L-selectin.
ICAM-1 is expressed on many types of cells, with its expression
up-regulated by proinflammatory cytokines in vitro (26).
Augmented ICAM-1 expression is also observed on keratinocytes,
fibroblasts, and infiltrating leukocytes in the inflamed skin in vivo
(52, 53). Furthermore, ICAM-1 expression by fibroblasts
may mediate neutrophil migration through fibroblast layers within
tissues (54, 55), and ICAM-1 expressed on lung epithelial
cells supports the adhesion and retention of neutrophils
(56). Therefore, it is possible that ICAM-1 expression on
cells other than endothelial cells might be involved in the migration
or retention of leukocytes within the perivascular area of inflamed
skin during the Arthus reaction. However, our finding that ICAM-1 was
expressed exclusively by skin endothelium in the Arthus reaction (Fig. 7) excludes this possibility. Moreover, this finding suggests that
endothelial ICAM-1 expression primarily mediates leukocyte accumulation
during the Arthus reaction.
Two dominant pathways contribute to initiation of the cutaneous Arthus
reaction: a FcRIII-dependent pathway and a complement-dependent
pathway using the C5aR (5, 6, 9). The loss of FcRIII
results in a 60% reduction in edema formation and neutrophil
recruitment compared with wild-type mice, whereas C5aR deficiency
results in a 30–50% reduction (5, 10). The present study
demonstrates that edema, hemorrhage, and neutrophil accumulation are
inhibited by 30–40% with L-selectin deficiency, 40–50% with ICAM-1
deficiency, and 50–60% with the combined loss of L-selectin and
ICAM-1 (Figs. 1 and 2A). Thus, blocking the function of
L-selectin, ICAM-1, or both adhesion molecules inhibits the Arthus
reaction to a similar extent as blocking either the C5aR or FcRIII
pathways. Thus, cell adhesion molecules, including L-selectin and
ICAM-1, may play a critical role in Arthus reaction initiation, in
addition to its progression. This suggests that L-selectin and ICAM-1
are potential therapeutic targets for human IC-mediated diseases such
as vasculitis syndrome and some collagen diseases. However, it should
be noted that genetic deficiency of L-selectin or ICAM-1 in the
development of Arthus reaction was a fundamentally different situation
than the selective inhibition of the function of these adhesion
molecules during the course of an IC-mediated disease.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Shinichi Sato, Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
3 Abbreviation used in this paper: IC, immune complex.
Received for publication October 16, 2001. Accepted for publication January 11, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-receptors in the Arthus reaction. Mol. Immunol. 36:893.[Medline]
RI/III and C5aR in the reverse Arthus reaction. J. Immunol. 164:1065.RIII (CD16) deficient mice. Immunity 5:181.[Medline]
: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J. Immunol. 137:245.[Abstract]
2- integrins: characterization of 2-integrins and ICAM-1 on HMC-1 cells. Scand. J. Immunol. 45:471.[Medline]
but not interleukin-1 induces polymorphonuclear leukocyte migration through fibroblast layers by a fibroblast-dependent mechanism. Immunology 74:107.[Medline]
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S. Szanto, I. Gal, A. Gonda, T. T. Glant, and K. Mikecz Expression of L-Selectin, but Not CD44, Is Required for Early Neutrophil Extravasation in Antigen-Induced Arthritis J. Immunol., June 1, 2004; 172(11): 6723 - 6734. [Abstract] [Full Text] [PDF]
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M. U. Norman, N. C. Van De Velde, J. R. Timoshanko, A. Issekutz, and M. J. Hickey Overlapping Roles of Endothelial Selectins and Vascular Cell Adhesion Molecule-1 in Immune Complex-Induced Leukocyte Recruitment in the Cremasteric Microvasculature Am. J. Pathol., October 1, 2003; 163(4): 1491 - 1503. [Abstract] [Full Text] [PDF]
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K. Komura, M. Hasegawa, Y. Hamaguchi, E. Saito, Y. Kaburagi, K. Yanaba, S. Kawara, K. Takehara, M. Seki, D. A. Steeber, et al. Ultraviolet Light Exposure Suppresses Contact Hypersensitivity by Abrogating Endothelial Intercellular Adhesion Molecule-1 Up-Regulation at the Elicitation Site J. Immunol., September 15, 2003; 171(6): 2855 - 2862. [Abstract] [Full Text] [PDF]
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K. Yanaba, Y. Kaburagi, K. Takehara, D. A. Steeber, T. F. Tedder, and S. Sato Relative Contributions of Selectins and Intercellular Adhesion Molecule-1 to Tissue Injury Induced by Immune Complex Deposition Am. J. Pathol., May 1, 2003; 162(5): 1463 - 1473. [Abstract] [Full Text] [PDF]
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J. M. Inal, B. Schneider, M. Armanini, and J. A. Schifferli A Peptide Derived from the Parasite Receptor, Complement C2 Receptor Inhibitor Trispanning, Suppresses Immune Complex-Mediated Inflammation in Mice J. Immunol., April 15, 2003; 170(8): 4310 - 4317. [Abstract] [Full Text] [PDF]
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Y. Shimada, M. Hasegawa, Y. Kaburagi, Y. Hamaguchi, K. Komura, E. Saito, K. Takehara, D. A. Steeber, T. F. Tedder, and S. Sato L-Selectin or ICAM-1 Deficiency Reduces an Immediate-Type Hypersensitivity Response by Preventing Mast Cell Recruitment in Repeated Elicitation of Contact Hypersensitivity J. Immunol., April 15, 2003; 170(8): 4325 - 4334. [Abstract] [Full Text] [PDF]
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