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* Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo; and
Department of Microbiology, School of Pharmaceutical Sciences, University of Shizuoka, Japan
Correspondence: Tatsuro Irimura, Ph.D., Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: irimura{at}mol.f.u-tokyo.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: adjuvant • cell migration • cytokine
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Epidermal LC have been shown to play an important role as antigen-presenting cells in the sensitization phase of delayed-type hypersensitivity (DTH) such as contact hypersensitivity [6 , 7 ]. In this context, it is important to note that LC are able to migrate, carrying antigen with them, from epidermal sites of sensitization to the draining lymph nodes. In the lymph nodes, LC become interdigitating dendritic cells in the T cell area and present antigen to T cells in association with major histocompatibility complex (MHC) class II molecules [8 9 10 ]. Another potential antigen-presenting cell during the sensitization phase of contact sensitivity is the dermal macrophage, although there is still some controversy over whether dermal macrophages are major antigen-presenting cells during the sensitization phase of DTH [5 , 11 12 13 14 ]. In addition, little attention has been paid to whether cellular trafficking of dermal macrophages and related cells takes place during the sensitization process, partly because of a lack of markers able to distinguish dermal macrophages.
Using mAbs specific for mMGL, we have previously obtained evidence suggesting that dermal cells expressing this lectin migrate from skin to draining lymph nodes during the sensitization phase of a contact sensitivity model in which mice were epicutaneously sensitized with fluorescein isothiocyanate (FITC) [15 ]. FITC was not detectable, however, in these cells. During this study we became aware of the effects on the efficacy of sensitization of the solvents (or vehicles) used to dissolve the antigen (FITC), and we discovered that epicutaneous application of solvents alone induced a transient increase in the number of mMGL-positive cells within the T cell area of draining lymph nodes. This phenomenon correlated positively with the efficacy of contact sensitization against antigen when we tested FITC dissolved in a variety of solvents.
Information obtained from cell transfer experiments [15 ] indicated that the increase in the number of mMGL-positive cells in the regional lymph nodes was probably due to migration of dermal cells expressing mMGL from the site of sensitization. However, we could not previously obtain direct evidence to demonstrate the mechanism by which solvents, such as a mixture of acetone and dibutylphthalate (AD), initiated migration of dermal mMGL-positive cells in situ. In the present study, we focused on the sites of skin sensitization in order to more closely investigate the trafficking of mMGL-positive cells. We showed that solvent alone induced migration of mMGL-positive cells and, using a newly developed ex vivo assay, demonstrated the involvement of soluble factors in the initiation of this migration.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Reagents
Biotin-conjugated mAb (mouse anti-rat 
and 
light chains
(anti-/) and streptomycin were purchased from Sigma Chemical (St.
Louis, MO); Dulbecco’s minimum Eagle’s medium (DMEM) was from Nissui
Pharmaceutical (Tokyo, Japan); fetal calf serum was from BioWhittaker
(Walkersville, MD); acetone, dibutylphthalate, and penicillin were from
Wako Pure Chemical (Osaka, Japan); alkaline phosphatase-conjugated
streptavidin, horseradish peroxidase-conjugated streptavidin, and
purified rat IgG were from Zymed Laboratories (South San Francisco,
CA); Histomark Red was from Kirkegaard & Perry (Gaithersburg, MD);
paraformaldehyde and glutaraldehyde were from Nacalai Tesque (Kyoto,
Japan); polyclonal sheep anti-digoxigenin Fab fragments were from
Boehringer Mannheim (Mannheim, Germany); and the FluoreLink-Ab Cy3.5
label kit was from Amersham (Aylesbury, UK). Culture supernatants were
prepared from rat hybridoma cell lines producing mAb against mMGL (mAb
LOM-14, IgG2b; and mAb LOM-8.7, IgG2a) in DMEM containing 4.5 g/L
glucose, 10% fetal calf serum, penicillin (100 U/mL), and streptomycin
(100 µg/mL); the mAbs were purified from these supernatants, as
described previously [3
]. Cy3.5-conjugated sheep
anti-digoxigenin Fab fragments and digoxigenin-conjugated mAb LOM-14
were prepared as described elsewhere [15
].
Biotin-conjugated anti-mouse F4/80 mAb was obtained from CALTAG
Laboratories (San Francisco, CA).
AD application
Solvent was applied to skin according to methods described
elsewhere [15
16
17
], with some modifications. Mouse
forelimb or abdominal skin was shaved clean with a small clipper and
treated epicutaneously with 200 µL of a 1:1 mixture of acetone and
dibutylphthalate (AD). Skin samples (typically 1 cm x 1 cm in
size) were collected, using scissors, from the site of AD application
at various times after application. Skin samples from untreated mice
were used as controls. In some experiments, AD was applied in
vitro to skin samples taken from untreated mice.
Skin organ culture
Mouse skin samples were subjected to short-term organ culture
according to published procedures [18
, 19
],
with modifications. A skin sample (
1 cm2, sensitized or
untreated) was placed on a polyethylene terephthalate membrane (pore
size 1.0 µm; Falcon® Cell Culture Inserts; Becton
Dickinson, Franklin Lakes, NJ) with the epidermal side up. The membrane
and skin sample were placed in a well of a six-well cell culture plate
(Falcon® 3046, Becton Dickinson), and serum-free ASF 104
medium (Ajinomoto, Tokyo, Japan) containing 100 U/mL penicillin and 100
µg/mL streptomycin (termed culture medium throughout this report) was
added so that the skin sample was maintained at the air/liquid
interface. Organ culture was carried out in a humidified 5%
CO2 atmosphere at 37°C.
Preparation and fractionation of conditioned medium (CM)
One hour after AD application, a mouse skin sample (typically
1 g) from the site of application was cut into small pieces, and
then the skin fragments were incubated in 5 mL of culture medium in a
cell culture dish for 24 h at 37°C in a humidified 5%
CO2 atmosphere. The supernatant was collected, centrifuged
at 1,000 rpm for 10 min, and then sterilized by filtration through a
membrane filter (0.2-µm pore size; Iwaki, Tokyo, Japan). The CM was
fractionated using a Centricon concentrator (Amicon, Beverly, MA).
Briefly, 2 mL of CM was centrifuged in a Centricon 10 for 30 min at
5,000 g. The filtrate and retentate were recovered
separately and made up to the original volume (2 mL) with culture
medium. These fractions were sterilized by filtration as above.
Treatment with anti-IL-1ß mAb or anti-blocking mAbs against mMGL
(LOM-8.7)
Skin samples prepared from the site of AD application were
subjected to organ culture in the presence of 100 µg/mL of
anti-IL-1ß mAb, normal hamster IgG as a control for the mAb, mAb
LOM-8.7, or rat IgG as a control for the mAb. After 2 h, the
antibodies were removed and incubation was continued for a further
24 h in fresh culture medium. The skin explants were then prepared
for microscopic analysis (see below).
Immunohistochemical detection of mMGL-positive cells
mMGL-positive cells were immunohistochemically detected as
described previously [1
]. In brief, skin samples
(freshly prepared from mice or recovered from organ culture) were
embedded in OCT Compound (Miles, Elkhart, IN) and frozen in a liquid
nitrogen bath. Cryostat sections (10 µm thickness) were picked up on
poly-L-lysine-coated slides, and fixed in acetone.
Nonspecific binding sites were blocked using a blocking solution [2%
normal goat serum and 3% bovine serum albumin (BSA) in Dulbecco’s
modified phosphate-buffered saline (DPBS: PBS containing 0.91 mM
CaCl2 and 0.49 mM MgCl2)] for 10 min at
20°C. After incubation with mAb LOM-14 (1/10 dilution in the blocking
solution) or with normal rat serum (1/50 dilution; negative control)
for 1 h at 20°C, the sections were fixed in 2% paraformaldehyde
in 0.1 M sodium phosphate (pH 7.0). The sections were further incubated
with biotinylated mAb mouse anti-rat / (1/50 dilution in 3%
BSA/DPBS) for 1 h, followed by incubation with alkaline
phosphatase-streptavidin (1/100 dilution in 20 mM Tris-HCl buffer (pH
7.6) containing 3% BSA and 0.15 M NaCl) for 1 h. Bound antibody
was detected using Histomark Red, and the cell nucleus was
counterstained in Mayer’s hematoxylin after post-fixation using 2%
glutaraldehyde in DPBS. The sections were observed under a light
microscope (TMD-300, Nikon, Tokyo, Japan). In immunofluorescence
experiments, cryostat sections were treated with digoxigenin-conjugated
mAb LOM-14 (1/100 dilution in the blocking solution), fixed with 2%
paraformaldehyde, and then treated with Cy3.5-conjugated sheep Fab
anti-digoxigenin (1/1000 dilution in 3% BSA/DPBS). The sections,
mounted in Vectashield (Vector Laboratories, Burlingame CA), were
observed with the use of a confocal microscope (MRC-1024, Bio-Rad,
Herts, UK) equipped with a krypton/argon laser. All experiments were
repeated at least three times.
Immunohistochemical detection of mMGL and F4/80 double-positive
cells
The method described by Inaba et al. [20
] was
used with slight modifications. Cryostat sections (10 µm thickness)
were picked up on poly-L-lysine-coated slides, and fixed in
acetone for 30 s at 20°C. Digoxigenin-conjugated mAb LOM-14 was
applied at 1 µg/mL at 20°C for 1 h. The sections were washed
with DPBS, and fixed with 2% paraformaldehyde diluted in DPBS. The
sections were further incubated with alkaline phosphatase-conjugated
sheep Fab anti-digoxigenin diluted in Tris-HCl buffer (pH 7.6) for 30
min. The sections were washed and alkaline phosphatase reaction
products were developed with a BCIP/NBT substrate kit (Vector
Laboratories). Biotinylated anti-mouse F4/80 mAb was then added. After
washing, horseradish peroxidase-conjugated streptavidin was diluted
1:100 and applied for 30 min. The sections were washed again and
peroxidase reaction products were developed by the addition of DAB
(Funakoshi, Tokyo, Japan). The sections were fixed again with 2%
glutaraldehyde in DPBS and examined under a microscope. All experiments
were repeated at least three times.
Immunohistochemical analysis of skin explants
The number of mMGL-positive cells stained with mAb LOM-14 was
counted within 50 different areas (6,650 µm2 each) that
were randomly selected in dermis from triplicate tissue sections. The
sections were viewed under a microscope at a magnification of x400.
The total number of mMGL-positive cells was determined in each area,
and the result were expressed as total mMGL-positive cell numbers ± SEM (n = 3). The statistical
significance of differences between experimental groups was calculated
using Student’s t test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Migration of mMGL-positive cells from AD-treated skin explants
The depletion of mMGL-positive cells from dermis was observed in
an ex vivo experimental system. Skin samples were subjected
to short-term culture [18
, 19
], and the
density of mMGL-positive cells in the dermis of the skin explant was
determined. The density of mMGL-positive cells in AD-treated dermis
gradually decreased (Fig. 3a
). In contrast to the in vivo experiments,
mMGL-positive cell numbers did not recover by 24 h after AD
application. As a control, skin explants that had not been subjected to
AD treatment were cultured under the same conditions. The number of
mMGL-positive cells in the untreated dermis remained constant for at
least 24 h (Fig. 3b)
, indicating that the depletion of
mMGL-positive cells from the dermis of AD-treated skin samples was not
due to degeneration of tissue during the culture period but to active
biological processes. The in situ and ex vivo
changes in the density of mMGL-positive cells in the dermis are
compared in Figure 3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
how the validity of the ex vivo
system.
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Requirement of the migration of mMGL-positive cells for AD
application in vivo
We subsequently examined whether AD treatment of skin after
excision could induce migration of mMGL-positive cells and production
of soluble factors. AD was applied in vitro to skin samples
prepared from untreated mice. Skin samples taken from AD-treated sites
and untreated samples from untreated mice were prepared as positive and
negative controls, respectively. The samples were cultured as described
above, and the density of mMGL-positive cells in dermis was compared
after in vitro incubation for 24 h. The number of
mMGL-positive cells did not change after in vitro
application of AD (Fig. 5a
). The inability of in vitro treatment to induce
migration of mMGL-positive cells was further confirmed by the
production of soluble factors responsible for the migration, as shown
in Figure 5b
.
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Morphological changes in mMGL-positive cells in situ
after AD application
We also investigated morphological changes in mMGL-positive cells
after AD application by confocal microscopy, using mAb LOM-14 for
immunofluorescence staining. Before AD treatment, mMGL-positive cells
had an irregular shape and a length of 10–20 µm (Fig. 7a
). At 4 h after AD application, some cells changed their
shape into an extended form, with a length of more than 30 µm (Fig. 7b)
. The number of mMGL-positive cells in the dermis appeared to have
decreased, consistent with the regular immunohistochemical analyses
(Figs. 1
and 2a)
. At 8 h after AD application, mMGL-positive cell
numbers were further decreased, and the remaining cells showed more
extended shapes (Fig. 7c)
. The results also indicated that there was no
down-regulation of mMGL expression upon AD application.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It is possible that depletion of mMGL signals in the dermal cells could be due to down-regulation of mMGL expression induced by AD application or soluble factors. We therefore investigated a common macrophage surface marker expressed by F4/80. We counted mMGL and F4/80 double- and single-positive cells after AD application. As shown in Figure 2 , the number of F4/80 single-positive cells decreased until 12 h after AD application, however, its decrease was small. In contrast to the slight decrease in the number of F4/80-positive cells, the number of mMGL-positive cells or mMGL-F4/80 double-positive cells decreased significantly until 12 h after AD application. We also purified mMGL-positive cells from mouse back skin, incubated these in fresh or conditioned culture medium for 24 h, and compared the levels of mMGL in cell lysates by immunoblot analyses using the mMGL-specific mAb LOM-14. No differences in the signal representing mMGL protein (a 42-kDa band) were observed among the lysates of freshly isolated cells, conditioned medium-treated cells, and cells incubated in fresh culture medium (data not shown). These results indicate that AD application does not down-regulate mMGL expression in mMGL-positive cells in the dermis, and strongly suggest that the observed depletion of mMGL-positive cells is due to cell migration from the dermis. It is interesting to note that mMGL-F4/80 double-positive cells may represent a migratory population, whereas F4/80 single-positive cells are stationary histiocytic macrophages.
Epidermal cells such as keratinocytes [25 ] and LC [26 ] have been shown to play pivotal roles in the skin sensitization phase of DTH. Keratinocytes, which make up approximately 95% of the cell mass of the epidermis, produce cytokines, including chemokines and adhesion molecules, that contribute to the initiation of both "antigen-independent" and "antigen-dependent" cutaneous inflammation. However, the contribution of dermal macrophages to DTH sensitization has not been substantially studied. Several investigators, using a keratomed skin strip method, isolated dermal macrophages from skin lacking its epidermis and found that these macrophages had the capacity to present antigen to T cells in vitro [12 , 13 ]. Others succeeded in in vivo antigen sensitization through the tape-stripped skin method, which also suggests a function for dermal macrophages as antigen-presenting cells [11 , 14 ]. However, it was shown in our previous studies that the epicutaneously administered antigen (FITC) was not co-localized with mMGL-positive cells [15 ]. Thus, these cells may not function as antigen-presenting cells. The potential immunomodulatory functions other than antigen presentation during the DTH response should be an interesting subject for future investigations.
The establishment of an ex vivo experimental system allowed
us to study mechanisms underlying the initiation of trafficking of
mMGL-positive cells. For example, we tested the involvement of mMGL
molecules. A blocking mAb inhibited the depletion of mMGL-positive
cells from dermis in skin explants, suggesting that mMGL molecules
contribute directly to the initiation of trafficking of these cells
upon sensitization. The ex vivo system also allowed us to
test for the involvement of soluble factors. It is well documented that
LC and keratinocytes produce cytokines, which regulate immune response
and inflammation [26
27
28
]. Thus, soluble factors
produced in the skin environment upon sensitization might be expected
to be involved in such migration. To address this possibility, we
prepared CM using AD-treated skin and tested its ability to induce
depletion of mMGL-positive cells from the dermis of untreated fresh
skin explants. The CM decreased the density of mMGL-positive cells in
the dermis of untreated skin in a dose-dependent manner (Fig. 4)
,
whereas CM prepared from untreated skin did not show this activity
(Fig. 5b) . It is likely that cytokines other than chemokines were
involved in the trafficking, because the depleting activity in the CM
was resistant to pertussis toxin (data not shown) and resided in the
fraction containing molecules with Mr >
10,000 Da (Fig. 4c) . Chemokine signaling is inhibited by pertussis
toxin [22
, 29
] because chemokine receptors
are G-protein-coupled [24
]. Incubation with anti-IL-1ß
antibodies significantly decreased the effect of AD treatment, strongly
suggesting that IL-1 produced in skin is involved in the migration of
mMGL-positive cells (Fig. 6)
. LC are known to produce IL-1ß, tumor
necrosis factor 
(TNF-), and IL-8 [21
22
23
], and
keratinocytes produce IL-1, IL-6, IL-15, TNF-, interferon-,
granulocyte-macrophage colony-stimulating factor, and transforming
growth factor ß after skin sensitization [30
].
Keratinocytes may also produce IL-1ß [31
].
An additional important point is that AD treatment failed to induce a decrease in mMGL-positive cell numbers when the solvent was applied onto skin explants after dissection (Fig. 5a) . This was also true for the production of soluble factors in CM (Fig. 5b) . These results clearly demonstrate that the AD-induced migration of mMGL-positive cells observed in in vivo or ex vivo experiments is based on a biological process that requires the integrity of the whole animal rather than local skin responses alone. For example, it is thought that neuropeptides participate in the regulation of DTH response [32 , 33 ]. Nerve systems and neurotransmitters released by sensitization may function initiators of trafficking of mMGL-positive cells and will also be a focus of future studies in our laboratory. The effect of anti-mMGL blocking mAb was also examined in experiments using AD-treated skin explants (Fig. 6) . The AD-induced decrease in mMGL-positive cell numbers in the dermis was inhibited by a blocking mAb but not by a non-blocking mAb. This result suggests that mMGL molecules are involved in the cell migration after reception of signals from soluble factors produced locally.
In conclusion, we demonstrated in both in vivo and ex vivo experiments that initiation of trafficking of mMGL-positive cells in skin is induced by AD treatment, and that soluble factors produced in the skin and mMGL molecules are both directly involved in this process.
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ACKNOWLEDGEMENTS |
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Received December 20, 1999; revised June 19, 2000; accepted June 22, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Arch. Dermatol. Res. 289,277-284[Medline]
-melanocyte stimulating hormone modulates contact hypersensitivity responsiveness in C57/BL6 mice J. Invest. Dermatol. 93,511-517[Medline]
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