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*
Center for Dermatology, Department of Medicine, University College London, London, United Kingdom; and
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1
are important signals governing this process, but
the potential regulatory role of IL-1 processing by caspase-1 is
unknown. In wild-type (WT) mice, application of the contact allergens
2,4-dinitrofluorobenzine and oxazolone lead to a marked reduction in
epidermal LC numbers, but in caspase-1-deficient mice this reduction
was not observed. Moreover, although intradermal injection of TNF-
(50 ng) induced epidermal LC migration in WT mice, this cytokine failed
to induce LC migration in caspase-1-deficient mice. Intradermal IL-1
(50 ng) caused a similar reduction in epidermal LC numbers in both WT
and caspase-1-deficient mice, indicating that, given an appropriate
signal, caspase-1-deficient epidermal LC are capable of migration.
Contact hypersensitivity to both 2,4-dinitrofluorobenzine and oxazolone
was inhibited in caspase-1-deficient mice, indicating a functional
consequence of the LC migration defect. In organ culture the caspase-1
inhibitor Ac-YVAD-cmk, but not control peptide, potently inhibited the
epidermal LC migration that occurs in this system, and reduced
spontaneous migration of LC was observed in skin derived from
caspase-1-deficient mice. Moreover, Ac-YVAD-cmk applied to BALB/c mouse
skin before application of contact sensitizers inhibited LC migration
and contact hypersensitivity in vivo. Taken together, these data
indicate that caspase-1 may play a central role in the regulation of LC
migration and suggest that the activity of this enzyme is amenable to
control by specific inhibitors both in vivo and in
vitro. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LC migration from epidermis to lymph node is a complex and tightly
regulated process, and current data suggest that IL-1 and TNF-
are key cytokine signals involved in this process (4, 5).
Intradermal injection of either cytokine in murine skin leads to rapid
LC migration from epidermis and subsequent accumulation of DC in
draining lymph nodes (6, 7). Moreover, both
anti-IL-1 and anti-TNF- neutralizing Abs inhibit
hapten-induced LC migration from murine skin in vivo (5).
Both cytokines are available in the epidermal microenvironment, where
TNF- may be produced by both keratinocytes (8) and LC
(9, 10, 11), although in murine skin IL-1 is primarily a
product of LC (12). It is clear also that keratinocytes
and LC express surface receptors for both cytokines and thereby can
respond appropriately to them (13, 14, 15).
The observation that contact sensitization can be inhibited by
intradermal injection of blocking anti-IL-1 Ab before topical
application of Ag (16) has led to particular interest in
defining the function of IL-1 family molecules in cutaneous immune
responses. This expanding family of structurally related cytokines has
central functions in host defense, including activation of endothelium
and induction of secondary mediators, such as GM-CSF and TNF-
(17). IL-1 is synthesized as an inactive 31-kDa
precursor molecule that requires cleavage by the cysteine protease
caspase-1 (previously known as IL-1-converting enzyme)
(18) to release biologically active mature 17-kDa
IL-1.
In view of the role of caspase-1 in regulating the processing and
release of IL-1 (18), we hypothesized that it might
represent a useful target for manipulation of LC migration. To this end
we have used caspase-1-deficient mice (19) and specific
caspase inhibitors to define the role of caspase-1 in experimental LC
migration and induction of murine contact hypersensitivity (CHS).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant murine IL-1 (sp. act., 1–2 x
108 U/mg) and TNF- (sp. act, 2 x
108 U/mg, by L929 cytotoxicity assay) were
purchased from R&D Systems (Oxon, U.K.) and Genzyme Diagnostics (West
Malling, U.K.), respectively. Biotin-conjugated rat anti-mouse
I-Ad/I-Ed mAb 2G9 and
streptavidin-FITC conjugates were purchased from PharMingen (San Diego,
CA). Caspase-1 inhibitor II (Ac-YVAD-cmk) and caspase-3 inhibitor III
(Ac-DEVD-cmk, a YVAD analog that does not inhibit caspase-1) were
obtained from Calbiochem (Beeston, U.K.), and all other reagents,
including contact sensitizers 2,4-dinitrofluorobenzine (DNFB) and
oxazolone (OX), were purchased from Sigma (Poole, U.K.) unless
otherwise indicated.
Animals
Caspase-1 knockout and wild-type (WT) littermate control mice were gifts from Dr. W Wong (BASF Corp., Worcester, MA) and have previously been described in detail (19). For caspase inhibitor experiments, female BALB/c mice were purchased from Harlan (East Sussex, U.K.). All animals were housed in a conventional animal facility with a 12-h light, 12-h dark cycle. Mice were used between 8 and 12 wk of age and in individual experiments were age-matched to within 2 wk. All experiments were conducted under provisions of the Animals (Scientific Procedures) Act, 1986.
Contact hypersensitivity
Groups of at least three mice were sensitized by application of 150 µl of 0.5% DNFB in acetone/olive oil (AOO; 4/1) to abdominal skin. Five days later, 10 µl of 0.25% DNFB was applied to dorsal and ventral surfaces of the right ear, and AOO alone was applied to the left ear. Twenty-four, 48, and 72 h later, challenge-induced ear swelling (relative to the vehicle-treated ear) was measured using a modified spring-loaded micrometer (Mitutoya, Tokyo, Japan). In parallel experiments OX was used in the same volumes, and diluent was used at concentrations of 1% (sensitization) and 0.5% (elicitation). In experiments to assess the effect of caspase-1 inhibitors on CHS, mice were pretreated with 300 µl of 400 µM Ac-YVAD-cmk, Ac-DEVD-cmk, or vehicle (DMSO) 1 h before application of sensitizer and 0, 2, 4, 6, and 8 h after sensitization. Care was taken to ensure that sensitizer was only applied to the pretreated area of skin. All experiments were performed a minimum of three times.
Immunohistochemical staining of LC
LC numbers and morphology were evaluated en face in epidermal sheets prepared as described previously (20). Briefly, ears were excised and split into dorsal and ventral halves using fine forceps. Dorsal ear halves were then incubated in 0.02 M EDTA at 37°C for 90 min to allow separation of epidermis and dermis. Epidermal sheets were carefully peeled away from dermis, washed twice in PBS, fixed in acetone at -20°C for 20 min, and washed again. Epidermal sheets were then incubated with rat anti-mouse I-Ad/I-Ed Ab diluted to 5 µg/ml in PBS with 0.1% BSA for 45 min at room temperature, washed, and subsequently incubated for an additional 45 min with FITC-labeled anti-rat Ig secondary Ab diluted 1/100 in PBS with 0.1% BSA. Following further washing, epidermal sheets were mounted whole in glycerol, slides were coded, and LC were counted in 10 high power fields in the central portion of the ear using an eye-piece with a calibrated grid and a fluorescence microscope (Axiophot, Zeiss, New York, NY). The evaluator was blinded to the nature of slides examined. Results are expressed as the mean ± SEM numbers of LC per square millimeter of epidermis. At least four ears were used per experimental group, and all experiments were performed a minimum of three times.
In vivo LC migration in response to DNFB
Dorsal mouse ear skin (four ears per experimental group) was painted with DNFB (0.5% in AOO) and harvested 4 h later. Epidermal sheets were then prepared and immunostained, and LC were counted as described above. In some experiments ear skin was pretreated with 10 µl of the caspase inhibitor Ac-YVAD-cmk or Ac-DEVD-cmk (200 µM in DMSO) 1 h before application of DNFB.
In vivo LC migration in response to IL-1 and TNF-
Cytokines were either supplied as or reconstituted in sterile
solutions of PBS containing 0.1% BSA as carrier protein. Mice (three
per group) received 30-µl (50-ng) intradermal injections of cytokine
into both ears. Controls included mice that had received an equivalent
volume of diluent with carrier protein alone or were untreated. Ears
were harvested either 0.5 h after TNF- injection or 4 h
after IL-1 or vehicle injection and were processed for
immunohistochemical evaluation of LC numbers. Previous studies have
shown these intervals to be optimal for evaluation of LC migration
induced by these cytokines in mice (7).
In vitro LC migration
Ears were excised and split into dorsal and ventral halves. The dorsal half only (which does not have cartilage attached) was placed in organ culture as previously described (21). Briefly, dorsal ear halves were floated individually on 2 ml of RPMI/10% FCS with or without caspase-1 inhibitor or control peptide (each at a final concentration of 100 µM) in 16-mm diameter wells of 24-well cluster trays (Costar, Cambridge, MA) and kept at 37°C in a 5% CO2 incubator. At 24 and 48 h, ear halves were removed, and epidermal sheets were prepared and analyzed for the presence of LC as described above.
Statistical analysis
The statistical significance of differences in means of experimental groups was calculated using two-tailed Student’s t test. Mean differences were considered to be significantly different when p < 0.05. All data are presented as the mean ± SEM, and error bars are indicated on figures where the SEM was >5% of the mean.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In view of previous data indicating that IL-1 is involved in CHS
(16), we first wished to determine whether
caspase-1-/- mice could be sensitized normally
to epicutaneously applied hapten. Thus,
caspase-1-/- and control mice were sensitized
epicutaneously on abdominal skin with DNFB and challenged on ear skin 5
days later. Although WT mice responded with a vigorous ear swelling
response as expected, significant attenuation of this response was
observed in caspase-1-/- animals (Fig. 1
a). A similar degree of
suppression was observed when OX, another potent allergen, was used,
indicating that this phenomenon is not Ag specific (Fig. 1b).
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To explore possible associations in
caspase-1-/- mice between impaired contact
sensitization and LC mobilization, experiments were performed in which
epidermal LC numbers were determined following exposure of mice to
DNFB. This allergen has previously been shown to induce rapid migration
of LC from murine epidermis (22). Although LC were present
in WT and caspase-1-/- epidermis with a similar
morphology (Fig. 2, a and
c), LC numbers in epidermal sheets from untreated
caspase-1-/- mice were significantly lower than
those in WT mice (573 ± 37 LC/mm2 in
caspase-1-/- mice compared with 670 ± 22
LC/mm2 in WT mice; p < 0.05;
n = 6 mice/group). In WT mice, application of DNFB lead
to a rapid decline in LC numbers to about 72% of resting levels (Fig. 3a), a reduction comparable to
that which we routinely observe in BALB/c mice following hapten
challenge. In contrast, DNFB treatment failed to provoke significant LC
migration in caspase-1-/- mice (Fig. 3b). Similar data were obtained using the alternate
sensitizer OX (not shown). Interestingly, although LC numbers did not
change in caspase-1-/- mice following
application of DNFB, their morphology did change in a manner typical of
allergen-induced activation, with shortening of dendritic processes and
an increase in intensity of MHC class II expression, changes also seen
in the WT mice (Fig. 2, b and d).
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Because LC migration in response to hapten is thought to be
largely dependent upon the availability of IL-1 and TNF-
(5), we next examined the response of LC in WT and
caspase-1-/- mice to intradermal injection of
these cytokines. In addition, we determined whether in
caspase-1-/- mice LC were capable of migration
and were not simply fixed in epidermis. In WT mice, both TNF and
IL-1 lead to a rapid decrease in LC numbers (Fig. 4a), but although
caspase-1-/- LC responded normally to IL-1,
they failed to migrate after injection of TNF- (Fig. 4b).
Clearly therefore, given the correct signal,
caspase-1-/- LC are capable of migration, but
are unable to do this after hapten stimulation alone.
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To determine whether pharmacological caspase-1 inhibition might
inhibit LC migration, we assessed the effect of Ac-YVAD-cmk, a
cell-permeable irreversible caspase-1 inhibitor (23, 24),
on LC migration from epidermis in organ culture. Previous data have
indicated that in vitro organ culture of skin results in migration of
LC from epidermis into dermis, where they accumulate in cords in
lymphatic vessels before passing into the culture medium
(25). Thus, dorsal ear skin from WT mice was cultured for
up to 48 h, and LC numbers were evaluated in the presence of
Ac-YVAD-cmk or a control peptide, Ac-DEVD-cmk, which has little effect
on caspase-1 function (24). In skin cultured in medium
alone there was a steady decline in epidermal LC numbers over 48 h
to 550 ± 35 LC/mm2, compared with 785
± 8 LC/mm2 in WT skin before organ culture (Fig. 5a). However, skin cultured in
the presence of 100 µM YVAD showed a significant reduction in this
decline (675 ± 24 LC/mm2 at 48 h;
p < 0.05), whereas control peptide had no inhibitory
effect (553 ± 12 LC/mm2 at 48 h; not
significant), indicating that inhibition of caspase-1 impairs LC
migration in vitro. Similar data were obtained from BALB/c strain mice
(data not shown), indicating that the requirement for caspase-1 in LC
migration is not a strain-specific phenomenon. In skin derived from
caspase-1-/- mice (Fig. 5B), a much
slower decline in LC numbers occurred, paralleling the effect seen in
WT mice in the presence of caspase-1 inhibitor, and addition of
caspase-1 inhibitor was without effect.
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Having demonstrated that Ac-YVAD-cmk inhibits LC migration in
vitro, we next determined whether a similar effect could be achieved in
vivo. Ear skin of BALB/c mice (n = 3) was painted with
200 µm of YVAD in DMSO 1 h before application of 0.5% DNFB in
AOO. Controls included application of DMSO alone or application of the
control peptide DEVD. As expected, DNFB alone lead to a mean 24%
decrease in epidermal LC numbers after 4 h (Fig. 6). DMSO alone had no effect on this
decrease, but pretreatment of skin with YVAD inhibited 67% of the
DNFB-induced fall (p < 0.05). Control peptide
DEVD was without effect. Similar data were obtained with OX (data not
shown), indicating that caspase-1 inhibition is able to block LC
migration in a non-Ag-specific way.
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), suggesting
that the migration inhibition demonstrated in Fig. 6
results in
functional inhibition of the CHS response.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-, and in this study we have extended these
observations to demonstrate that caspase-1 is central to this
event. Initial characterization of caspase-1-deficient mice demonstrated that resting numbers of epidermal LC were significantly decreased in these animals compared with those in wild-type controls. Despite recent interest, the dynamics of LC recruitment to epidermis are unclear, although mechanisms must exist to ensure that LC precursors home to epidermis in correct numbers and at appropriate times (26). Our observations imply that caspase-1 or caspase-1-dependant cytokines are required for optimal LC homing to skin. An alternate explanation is that caspase-1-/- LC circulate constitutively out of epidermis more rapidly in the absence of caspase-1, and a lower steady state number is thereby achieved. However, this is argued against by our finding that in almost all circumstances examined by us, LC are less able to migrate in the absence of caspase-1 than they might normally do.
Our data demonstrate that LC migration in response to an antigenic
stimulus is defective in caspase-1 knockout mice. Similarly, TNF-, a
cytokine that in wild-type mice is known to lead to rapid mobilization
of LC, failed to induce migration in mice lacking caspase-1.
Importantly, however, migration in response to intradermal injection of
IL-1 was normal in caspase-1 knockouts. Collectively, these data
indicate that caspase-1 (or caspase-1-dependant cytokines) is required
for normal migration of LC and that in caspase-1 knockout mice there is
no generalized inability of LC to migrate if appropriate stimuli are
available. These data are consistent with the hypothesis that LC
migration requires the effective induction of two independent cytokine
signals supplied by TNF- and IL-1 (5). The
implication is that in caspase-1 knockout mice TNF- alone is unable
to initiate LC mobilization because the absence of caspase-1 results in
an inability of epidermal cells to inducibly or constitutively secrete
IL-1. In contrast, exogenous IL-1 is able to stimulate migration
because in addition to directly supplying one signal to LC, it is able
to induce production, probably by keratinocytes (8), of
TNF-. Thus, these findings confirm and extend those of Enk et al.
(16), who demonstrated that blockade of IL-1 by Ab
injection inhibits both LC migration and the CHS response. That TNF-
also plays a critical role has been demonstrated both by Ab inhibition
studies and in mice deficient in its p75 receptor (15, 27).
It is instructive that topical exposure of caspase-1 knockout mice to DNFB induced in epidermal LC an activated phenotype, as indicated by increased expression of MHC class II, despite failing to initiate mobilization. These data reveal that at least some degree of LC activation can be achieved in the absence of caspase-1 or caspase-1-dependant cytokines.
Caspase-1 is present in both LC (28) and keratinocytes
(29), although whether it is required in one or both cell
types for LC migration to occur requires further investigation.
Previous data demonstrating that IL-1 is primarily a product of LC
in murine skin and that caspase-1 is involved in IL-1 processing in
these cells (28) suggest that it is likely to be of
primary importance in LC, although our current data cannot exclude a
role for caspase-1 in keratinocytes. Indeed, recent evidence suggests
that caspase-1 in keratinocytes may be active in certain states and
result in the release of biologically active IL-1
(29).
Caspase-1 plays a role in the activation of at least two structurally
related cytokines, IL-1 and IL-18. Our results do not differentiate
between the two cytokines, and although a considerable body of evidence
suggests that IL-1 plays an important role in LC migration
(16), it is not at present clear whether IL-18 is also
involved in this process. Our observation that contact sensitivity to
both DNFB and OX is suppressed in the caspase-1 knockout mice is of
interest in this regard, as two independent groups have reported
previously that epicutaneous CHS is normal in IL-1 knockout mice
(30, 31). Only when Ag was injected intradermally could
suppression of delayed-type hypersensitivity be observed
(30). Were IL-1 the only caspase-1-dependant cytokine
involved in LC migration we would expect to have seen similar
preservation of epicutaneous CHS in our mice. One explanation for this
discrepancy may be that in some situations other molecules may
compensate for the absence of IL-1. The suppression of CHS observed
by us in caspase-1-/- mice suggests that any
non-IL-1 pathway is also caspase-1 dependant and may therefore
involve IL-18, the only other cytokine known to be processed by
caspase-1. An alternate explanation is that the experimental conditions
used by Shornick et al. (30), with a high concentration of
eliciting OX, masked a true suppression of CHS. Whatever the reason,
further study of this issue is required, and the observation that DTH
is impaired in IL-1-deficient mice is compatible with our current
model of the signals involved in LC migration.
In recent years a number of caspase-1 inhibitors have been described. Our study demonstrates that both in vitro and in vivo, Ac-YVAD-cmk, a prototypic caspase-1 inhibitor, is able to efficiently block LC migration. Short-term organ culture largely recapitulates normal LC migration in vitro (4, 21), with accumulation of LC in cords within dermal lymphatic vessels and subsequent exit into the culture medium. This process is likely to result from release of IL-1 and/or TNF from injured keratinocytes, and our finding with skin derived from caspase-1-deficient mice and with caspase-1 inhibitors in BALB/c skin indicates that it is clearly caspase-1 dependant. Moreover, topical application of YVAD in vivo resulted in a marked inhibition of LC migration in response to topical DNFB and effectively inhibited CHS. Clearly, therefore, YVAD is able to penetrate the epidermis and interact with caspase-1 inside viable epithelial cells, and we are currently exploring the possibility of using such compounds as cutaneous immune modulators in vivo.
LC migration from epidermis is a critical first step in the initiation of an Ag-specific immune response in skin. The data presented here indicate that caspase-1 is central in this process and is amenable to control by specific inhibitors in vivo and in vitro. These observations may have important implications for future therapeutic control of Ag-specific skin diseases, including allergic contact dermatitis, atopic eczema, and psoriasis.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Richard Groves, University College London Center for Dermatology, 7th Floor Jules Thorn Institute, Middlesex Hospital, Mortimer Street, London, W1T 3AA U.K.
3 Abbreviations used in this paper: LC, Langerhans cell; DC, dendritic cell; DNFB, 2,4-dinitrofluorobenzene; OX, oxazolone; AOO, acetone olive oil; WT, wild type; CHS, contact hypersensitivity.
Received for publication July 6, 2000. Accepted for publication January 2, 2001.
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), but there was significant suppression of this response in
caspase-1-deficient animals (
). *, p < 0.05;
**, p < 0.01. Unsensitized controls (
, WT;
, caspase-1 deficient) demonstrated negligible ear swelling.
n = 3 mice/group. The results are representative of
three independent experiments.
