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Regulates Corneal Langerhans Cell Migration1
Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mediates
corneal LC migration and to establish the interaction of IL-1 and
TNF- in regulating LC migratory capacity, we utilized gene-targeted
knockout mice lacking IL-1 receptor I (IL-1RI-/-), TNF
receptor I (p55-/-), TNF receptor II
(p75-/-), or both
(p55-/-p75-/-). LC migration was induced by
thermal cautery or cytokine injection and enumerated by an
immunofluorescence assay. Migration of LC after cauterization and
TNF- injection was significantly depressed in both
p55-/- and p75-/- mice. Similarly, in the
first 72 h after intracorneal injection of IL-1, LC migration
was reduced in p55-/-, p75-/-, and
p55-/-p75-/- mice. In contrast, injection
of TNF- in IL-1RI-/- mice led to normal migration of
corneal LC indistinguishable from wild-type controls. These results
suggest that the IL-1 induction of corneal LC migration is largely
mediated by TNFR function, whereas TNF- induction of LC migration is
independent of IL-1RI activity. Moreover, the data suggest that both
p55 and p75 signaling pathways are important in mediating LC migration
in the cornea. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the setting of corneal transplantation, the presence of LC in the donor cornea has been shown to effect host allosensitization and graft rejection (9). Since in clinical corneal transplantation patients receive central corneal buttons devoid of LC, it is believed that corneal allografts may instead be recognized through the "indirect" pathway of allorecognition involving activation and migration of recipient LC from the limbus to the donor corneal tissue where they can acquire foreign Ag (10, 11). Two lines of indirect evidence suggest that LC migration is a critical element in host allosensitization. First, the number of infiltrating host LC in the graft bed is predictive of the swiftness with which the host acquires donor-specific delayed type hypersensitivity (12), and the promotion of corneal allograft survival by IL-1 receptor antagonist (IL-1ra) has been correlated with suppression of LC migratory capacity (13). Beyond these observations in experimental models of corneal transplantation, migration of limbal LC into the cornea has been associated with loss of ocular immune privilege (14) and other immunoinflammatory events in the cornea such as development of herpetic keratitis (8, 15, 16, 17, 18, 19).
The mechanisms involved in regulation of corneal LC migration are
incompletely understood. Several cytokines have been implicated but
only the role of IL-1 has been extensively studied (9, 14, 20, 21).
However, the close cross-regulation of IL-1 and TNF- in multiple
models of inflammation, and the fact that stimulation of central
corneal tissue results not only in IL-1 but also in TNF- expression
from resident epithelial cells (22) makes TNF- a candidate for study
in regulation of corneal LC migration. Moreover, it has recently been
shown that TNF- plays a role in the migration of dendritic cells in
the skin (23, 24, 25).
TNF- is a pleiotropic cytokine that mediates a large number of
proinflammatory functions such as up-regulation in the expression of
adhesion and costimulatory molecules, neutrophil activation, induction
of chemokine secretion and activation of the NF-
B signal
transduction pathway (26, 27). TNF- activity is regulated by two
distinct receptors, the type I receptor (p55) and the type II receptor
(p75), which have largely homologous extracellular domains but distinct
intracellular domains that can mediate discrete cellular responses (28, 29). To determine whether the genetic deficiency of either, or both,
TNF receptors could affect corneal LC migration, mutant mice were
exposed to different corneal stimuli that efficiently induce LC
migration in wild-type mice. Furthermore, experiments were conducted to
determine whether the well-known induction of LC migration by IL-1 is,
at least in part, mediated by TNF-. Our results suggest that the
signaling pathways of both TNF receptors are important in mediating
corneal LC migration. These data also suggest that IL-1 induction of LC
migration is largely mediated by TNF- receptor activity and,
conversely, that TNF- can activate corneal LC migration
independently of IL-1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male mice 6 to 8 wk old with homozygous genetic deficiency of
either one TNF- receptor (TNFRI-KO (p55-/-), TNFRII-KO
(p75-/-)), both TNF- receptors (double TNFR-KO
(p55-/-p75-/-)), or the IL-1 receptor I
(IL-1RI-KO (IL-1RI-/-)) and their wild-type controls
(C57BL.129 for p55-/- and
p55-/-p75-/-; and C57BL/6 for
p75-/- and IL-1RI-/-) were bred in the
Schepens Eye Research Institute Animal Colony. Breeder pairs of
knockout (KO) animals were provided as follows: TNFRI-KO
(p55-/-) and double TNFR-KO
(p55-/-p75-/-) mice by F. Hoffmann-La Roche
AG, Basel, Switzerland; TNFRII-KO (p75-/-) mice by
Genentech, San Francisco, CA. All animals were treated according to the
Statement for the Use of Animals in Ophthalmic and Vision Research by
the Association for Research in Vision and Ophthalmology. Each animal
was anesthetized with an intramuscular injection of 3–4 mg of ketamine
and 0.1 mg of xylazine before surgical procedures. Each protocol at
each time point was performed on 10 murine corneas and replicated once;
representative data are presented herein.
Thermal cautery of the corneal surface and intracorneal cytokine injections
Mice were anesthetized and placed under the operating
microscope. Using the tip of a hand-held cautery, five burns were
applied to the central 50% of the cornea to induce centripetal LC
migration (6). Erythromycin ophthalmic ointment was applied immediately
following surgery. Two weeks after cauterization, which correlates with
the maximal LC migration response in this model (14), corneas were
harvested and LC enumeration was performed as detailed below. For
cytokine injections, a microsurgical blade (Superblade 30°, Kabi
Pharmacia Ophthalmic Inc, Franklin, OH) was used to make a
horizontal 50% thickness intrastromal incision in the central cornea.
After forming a tunnel in the stromal tissue, cytokine was injected by
use of a 33-gauge needle (Delasco, Tokyo, Japan). Recombinant
murine IL-1 (1 ng, R&D Systems, Minneapolis, MN) or recombinant
murine TNF- (10 pg–1 ng, R&D Systems) were injected. Endotoxin
levels were <0.1 ng/µg of recombinant cytokine for all samples by
Limulus amoebocyte lysate assay. Cytokine preparations were
diluted in PBS to achieve the desired dose in a 1-µl injection; and
controls received intracorneal injections of 1% PBS alone. In
addition, to ensure that the induction of LC was cytokine specific and
not due to potential endotoxin contamination, additional controls
included injections of heat-inactivated (15 min at 100°C) TNF- and
IL-1 cytokine preparations into wild-type controls
(n = 5 per strain). At specified time points, corneas
were harvested and LC enumeration was performed as described below.
Langerhans cells enumeration
LC were enumerated in whole corneal epithelial sheets by use of indirect immunofluorescence assay, as described previously (14). Briefly, at 24 h, 72 h, and 1 and 2 wk following corneal stimulation (cautery or intracorneal cytokine injection), murine eyes were collected and the corneas were dissected. Corneas were placed in 20 mM EDTA buffer and incubated for 30–40 min at 37°C. The epithelium was detached and washed in PBS at room temperature. Epithelial sheets were fixed with 95% alcohol for 30 min. After two washings in PBS for 10 min, epithelial sheets were incubated with 1/15 diluted primary anti-murine Iab Ab for 45 min at 37°C. Controls bypassed this step or were incubated with an unrelated (e.g., anti-Iad) Ab as previously described (14). Epithelial sheets were washed twice in PBS for 10 min and incubated with 1/10 diluted fluorescein isothiocyanate-labeled goat anti-mouse secondary Ab for 30 min at 37°C (PharMingen, San Diego, CA). Samples were mounted on slides and immediately examined under the fluorescent microscope. Langerhans cells were then enumerated using a square ocular grid.
Statistical analysis
Comparison of the mean number of LC between different mouse strains, as well as between treatment protocols, was made using the Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether TNF receptor activity could influence LC
migration into the cornea, 1 ng of TNF- was injected into the
corneal center of wild-type and TNFR-KO mice. In companion experiments,
thermal cautery was applied to murine corneas to determine the role of
TNFR in mediating LC migration in a standardized experimental model of
corneal inflammation (6), and the number of centripetally migrated LC
was determined following corneal stimulation. One week subsequent to
TNF- injection (Fig. 1
), the number of
LC in all three TNFR KO models was significantly depressed
(p < 0.001) as compared with wild-type
corneas, suggesting that deficiency in either p55 or p75 can profoundly
attenuate the LC migratory response. Similarly after corneal
cauterization, the number of central LC was significantly reduced in
the absence of either TNFR-I or TNFR-II activity as compared with
wild-type controls (Fig. 2A;
p < 0.01).
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, but not
heat-inactivated cytokine, to wild-type mice not only induced migration
of LC into the central cornea but also led to a significant increase in
the number of recruited LC at the corneal limbus which serves as a
potential reservoir for the corneal LC. However, in
p55-/- animals lacking TNFR-I activity, there was only
minimal increase in the LC number at the corneal limbus after
stimulation (Fig. 2
B), suggesting that TNFR-I may play a
critical role in mediating LC recruitment to the limbus from the
intravascular compartment after corneal stimulation.
TNF- induction of LC migration is independent of IL-1
It has been shown that centripetal LC migration can be induced by
IL-1 secretion by corneal epithelial cells or by direct injection of
IL-1 into the cornea (20, 21). It is not known, however, whether
TNF- induction of LC migration is dependent on IL-1 activity. To
determine whether TNF- can induce centripetal LC migration even in
the absence of IL-1 activity, different amounts of TNF- were
injected into the central cornea of IL-1RI-/- mice, and
the central corneal LC were enumerated. As shown in Fig. 3, TNF- was able to induce significant
centripetal migration of LC in a dose-dependent manner even in the
absence of IL-1RI activity, suggesting that IL-1 activation is not
necessary for mediating the TNF- effect on LC migration. Moreover,
to determine whether the induction of LC migration by TNF- is, at
least in part, affected by IL-1RI activity, TNF- was injected into
IL-1RI-/- and wild-type mice, and the corneal LC were
enumerated at different time points. The data demonstrate that the
activity of TNF- in promoting centripetal LC migration is identical
among the two groups (Fig. 4), suggesting
that the TNF- effect on LC migration is independent of IL-1RI
activity.
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The data above demonstrate that activation of the IL-1 system via
IL-1RI is not critical for TNF--mediated LC migration. Therefore, to
further delineate the cross-regulation between these two cytokine
systems, we wanted to test the converse; namely, whether IL-1 induction
of LC migration is under TNF- regulation. A known corneal LC
chemoattractant, IL-1 was injected into eyes of
p55-/-, p75-/-, and
p55-/-p75-/- mice. In addition, both active
and heat-inactivated IL-1 was injected into the corneas of wild-type
mice as controls. Heat-inactivated cytokine failed to induce LC
migration (data not shown). Our data from IL-1 injection into
TNFR-KO animals showed that particularly in the first 72 h,
deficiency in either TNFR activity led to significant suppression of LC
migration in response to cytokine as compared with wild-type controls,
and this effect was most profound when both TNF receptors were depleted
(Fig. 5). At 1 wk after stimulation, only
p55-/-p75-/- (and to a lesser extent
p55-/-) mice showed suppressed response to injected
IL-1. The data suggest that early induction of LC migration by IL-1
is largely under the regulation of TNF- receptors and that combined
deficiency of both TNFRs leads to a sustained suppression of
IL-1-induced LC migration.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the migration of LC into the central cornea appears to be an
important step in initiating immune responses, the mechanisms that
mediate this process remain incompletely understood. In the skin, the
role of TNF- in inducing dendritic and LC migration and cutaneous
inflammation has been extensively studied. Whereas it has been
demonstrated that TNF- promotion of cutaneous inflammation is
largely mediated by p55 (34), investigators have shown that TNF-
promotes migration of cutaneous dendritic cells primarily through the
selective activation of p75 (23, 24). In the cornea, significant
expression of TNF- by the corneal resident cells can be induced by
inflammatory stimuli (22), and the expression of a number of chemokines
(e.g., RANTES, monocyte chemoattractant protein, macrophage
inflammatory protein) can be under the regulation of locally
produced TNF- (35, 36, 37). The current series of experiments were
performed to determine whether TNF- activity is critical in
mediating corneal LC migration.
Our data demonstrate that in the absence of functional TNF-RI or
TNF-RII, the number of central LC after corneal stimulation with
TNF- or cautery are significantly lower than in wild-type controls.
Moreover, because deficiency in either TNFR can so profoundly
down-modulate LC migration into the central cornea in response to
stimulation, the data suggest that the two receptor systems, as is seen
in other models of inflammation (29), mediate largely discrete
functions that in this model independently contribute to inducing LC
migration. Our results also suggest that TNF- can induce its effect
on corneal LC migration in an IL-1-independent fashion. Our data show
that TNF- can induce a dose-dependent effect on corneal LC
recruitment even in IL-1RI-deficient mice, suggesting that TNF- is
sufficient to induce LC migration even with a defective IL-1 system at
all time points studied. Having demonstrated that the effect of TNF-
on LC is largely independent from IL-1, we tested the converse, namely,
whether IL-1 can induce corneal LC recruitment independently of TNF-
receptor function. Our data show that IL-1-induced migration of
corneal LC can be significantly impaired in the absence of TNF-RI,
TNF-RII, or both receptors, suggesting that the well-known effect of
IL-1 on early LC recruitment in the cornea after an inflammatory insult
is at least in part mediated by TNF-. Interestingly, 1 wk after
injection of IL-1, there was no appreciable effect of either TNF-RI or
TNF-RII deficiency on IL-1-induced LC migration, whereas the
suppression of LC migration was still highly appreciable among the
p55-/-p75-/- mice, suggesting some degree
of functional redundancy between the two TNF receptor subtypes, or
other compensatory mechanism, in animals devoid of just one type of
TNFR. Hence, in the aggregate, the data suggest that while p55 and p75
play discrete roles in effecting corneal LC migration, there is likely
also some functional redundancy between the two receptor systems.
It is important to emphasize the limitations of this study. First, our
studies have focused exclusively on epithelial LC, since the vast
majority of LC in both humans and rodents are in this layer of the
cornea and limbus. Nevertheless, it is important to appreciate that
there are a very few LC, based on morphological criteria, that can also
be identified in the anterior stroma of the cornea subsequent to
corneal stimulation. Whether the functional role or regulation of these
cells differs from that of the large number of LC seen in the
epithelium remains unknown. Second, it is critical to appreciate that
while our data suggest a prominent role for TNF- and IL-1 in
effecting corneal LC migration, we caution that the data should not be
taken as suggestions that these cytokines effect LC migration directly.
It is known that the recruitment of leukocytic populations, including
dendritic cells, relies on an intricate interaction between the
activation of adhesion molecules (e.g., CD44) and chemoattractants
(38). The critical role of TNF- and IL-1 in regulating the
expression of these adhesion and chemotactic factors in a large number
of clinical and experimental settings is now widely appreciated (36).
Since both of these proinflammatory cytokines are overexpressed early
after an inflammatory insult, one may speculate that TNF--induced
activation of nonlymphoid (e.g., resident corneal) cell NF-B
response elements can promote the expression of a wide array of
chemokines (26, 27, 36) and adhesion factors that may themselves
mediate LC migration (39, 40). A similar indirect role for TNF- has
been proposed as a possible mechanism in TNF--induced migration of
cutaneous LC (41).
Lastly, it is important to recognize that the molecular processes that mediate corneal LC migration may differ from those that mediate LC migration elsewhere, as in the skin. In addition to the lack of a constitutive population of LC, the normal cornea unlike the skin is avascular and devoid of lymphatics. Moreover, intraepithelial (horizontal) migration of LC in the cornea differs considerably from that seen in the skin where the LC migrate into and out of the epidermis (vertically) via the dermis (3, 4, 5, 6, 7, 8). This factor may explain the relevance of p55 functionality in corneal LC migration, since p55 is the major from of TNFR expressed by keratocytic/epithelial populations (42). Hence, one may speculate that p55-mediated expression of epithelial chemotactic and adhesion factors can participate in effecting LC migration (42).
Molecular strategies designed to target selective mediators of
inflammation have the potential of obviating some of the concerns
shared in relation to local and systemic toxic side effects of
nonspecific immunosuppression. One of the hurdles in development of
these molecular strategies is the significant functional overlap that
can exist among different ligands and receptor systems. The data
presented herein suggest that while in fact both the IL-1 and TNF-
systems can induce corneal LC migration, the IL-1-mediated induction of
the migration of these important APCs is largely dependent on the
functional activity of the TNFR system. These findings merit further
study in disease models as possible strategies to modulate
immunoinflammatory responses in the cornea and ocular anterior segment.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. M. Reza Dana, Laboratory of Immunology, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114. E-mail address:
3 Abbreviations used in this paper: LC, Langerhans cell; IL-1RI, IL-1 receptor type I; IL-1ra, IL-1 receptor antagonist; KO, knockout; TNF-, tumor necrosis-; TNFR, TNF receptor.
Received for publication July 30, 1998. Accepted for publication December 29, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by explants of mouse cornea. Invest. Ophthalmol. Vis. Sci. 37:1302. is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization. Immunology 84:31.[Medline]
and interleukin-1ß for migration. Immunology 92:388.[Medline]
-induced skin inflammation. Eur. J. Immunol. 27:1713.[Medline]
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