Blood, 1 December 2002, Vol. 100, No. 12, pp. 3853-3860
REVIEW ARTICLE
Leukocyte extravasation: chemokine transport and presentation
by the endothelium
Jim Middleton,
Angela M. Patterson,
Lucy Gardner,
Caroline Schmutz, and
Brian A. Ashton
From the Leopold Muller Arthritis Research Centre,
Centre for Science and Technology in Medicine, Keele University at
Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry,
United Kingdom.
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Abstract |
At sites of inflammation and in normal immune surveillance,
chemokines direct leukocyte migration across the endothelium. Many cell
types that are extravascular can produce chemokines, and for these
mediators to directly elicit leukocyte migration from the blood, they
would need to reach the luminal surface of the endothelium. This
article reviews the evidence that endothelial cells are active in
transcytosing chemokines to their luminal surfaces, where they are
presented to leukocytes. The endothelial binding sites that transport
and present chemokines include glycosaminoglycans (GAGs) and possibly
the Duffy antigen/receptor for chemokines (DARC). The binding residues
on chemokines that interact with GAGs are discussed, as are the
carbohydrate structures on GAGs that bind these cytokines. The
expression of particular GAG structures by endothelial cells may lend
selectivity to the type of chemokine presented in a given tissue,
thereby contributing to selective leukocyte recruitment. At the luminal
surface of the endothelium, chemokines are preferentially presented to
blood leukocytes on the tips of microvillous processes. Similarly,
certain adhesion molecules and chemokine receptors are also
preferentially distributed on leukocyte and endothelial microvilli, and
evidence suggests an important role for these structures in creating
the necessary surface topography for leukocyte migration. Finally, the
mechanisms of chemokine transcytosis and presentation by endothelial
cells are incorporated into the current model of chemokine-driven
leukocyte extravasation.
(Blood. 2002;100:3853-3860)
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Introduction |
A central feature of inflammatory diseases is
the migration of leukocytes from the circulation, across the
endothelium and the basement membrane, and into the affected tissue.
This mechanism of extravasation is induced by chemokines
(chemoattractant cytokines), which are a family of proinflammatory
mediators produced at the inflammatory site.1,2 As part of
the migration process, circulating leukocytes must first adhere to the
luminal surface of the endothelium. According to the current paradigm,
this interaction involves the sequential engagement of leukocyte and
endothelial adhesion molecules. First, selectins and their carbohydrate
counterligands mediate leukocyte tethering and rolling. Then, leukocyte
integrins and their ligands, including immunoglobulinlike intercellular
adhesion molecules, mediate firm leukocyte adhesion.3
Chemokines play a role in firm adhesion by activating integrins on the
leukocyte cell surface.4,5 The leukocytes are directed by
chemoattractant gradients to migrate across the endothelium, and
through the extracellular matrix into the tissue.
The intent of this review is to focus on the endothelium and its role
in transcytosing and presenting chemokines to blood leukocytes,
resulting in leukocyte extravasation. The molecular nature of the
endothelial binding sites that are proposed to transport and present
chemokines are discussed. The mechanisms of chemokine transcytosis and
presentation by endothelial cells are then fitted into the current
model of how leukocytes emigrate into tissues at sites of inflammation.
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Chemokine-binding sites on the endothelium |
It has been traditionally held that chemoattractants stimulate
directional leukocyte migration (ie, chemotaxis) by soluble gradients.
However, it has been suggested that soluble chemokine gradients are
unlikely to exist at the luminal endothelial surface, where chemokines
would be washed away by the blood.6,7 In addition, soluble
chemokines could activate leukocytes in the circulation prior to their
selectin-mediated adhesion to the endothelium, resulting in loss of
subsequent interaction with the endothelium and emigration. Therefore,
it has been proposed that chemokines could act in a bound form,
immobilized on the luminal endothelial surface where they exert their
proadhesive and migratory effects on blood
leukocytes.6,7
Experimental evidence for the hypothesis that chemokines can act in a
bound form has come from the findings that specific and saturable
chemokine-binding sites exist in situ on the venular endothelium of
human skin and synovium, and immobilized interleukin-8 (IL-8) (also
designated CXC ligand-8 [CXCL-8]) (Table
1) attracts leukocytes in
vitro.8,9 These sites are multispecific since a CXC
chemokine, such as IL-8, can be displaced by a CC chemokine, such as
RANTES, suggesting that the sites are not classic chemokine receptors
but may be other binding proteins or carbohydrates (as discussed
below). Electron microscopy has shown that when IL-8 and RANTES are
injected into the skin, they are bound at the abluminal surface of the
endothelium, internalized into caveolae (plasmalemmal vesicles), and
transported transcellularly to the luminal surface.10 Here
the chemokines are presented on the external aspect of the membrane to
blood leukocytes. The endothelial binding sites that function in IL-8
transcytosis and presentation interact with the C-terminus of the
chemokine, since a C-terminal truncation of IL-8 is neither
significantly transcytosed nor presented. Using intact IL-8, we
found approximately 10 times more immunolabel at the luminal
endothelial surface compared with the truncated chemokine, suggesting
that the majority of the chemokine is presented to leukocytes in a
bound, rather than free, form. The functional significance of the
chemokine transport and presentation is evident since C-terminally
truncated IL-8 shows reduced chemotactic activity in vivo and in
vitro.10 Similar transport and presentation mechanisms have been shown for ELC in the high endothelial venules of lymphoid tissue,11 suggesting that these mechanisms function in
normal immune surveillance as well as inflammation.
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Table 1.
Chemokines mentioned in this review together with their
alternative names, according to a recent classification system, and
their receptors
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Many of the cell types that produce chemokines are extravascular. Thus,
abluminal-to-luminal chemokine transcytosis and presentation by
endothelial cells provide a posting mechanism, enabling the chemokines
to reach the blood-endothelial interface and stimulate leukocyte
emigration.12 Candidate endothelial molecules involved in
chemokine transport and presentation include glycosaminoglycans (GAGs)
and the Duffy antigen/receptor for chemokines (DARC), and these are
further discussed below. Endothelial cells themselves can produce
chemokines, in which case these mediators may be pesented to leukocytes
at the endothelial cell surface but not transcytosed. One particular
chemokine produced by the endothelium is fractalkine, which carries the
chemokine domain on top of an extended mucinlike stalk.13
It exists as a membrane-anchored form and a shed soluble form and can
induce both adhesion and emigration of leukocytes.
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The molecular nature of the chemokine transporters/presenters:
glycosaminoglycans |
GAGs are polysaccharides with a high negative charge that is due
to sulfate and carboxyl groups and are usually attached to core
proteins to form proteoglycans. Since chemokines are largely basic
molecules, they exhibit electrostatic interactions with GAGs,
especially heparin and heparan sulfate.14 The main GAG expressed by endothelial cells is heparan sulfate. Heparan sulfate proteoglycans compose 50% to 90% of total endothelial
proteoglycans.15 Some of these proteoglycans, such as
syndecan, glypican, and CD44, are membrane-associated glycoproteins
while others, such as perlecan, are found in the basement membrane. The
dissociation constant (Kd) of the GAG-chemokine
interaction has been variously reported in the low nanomolar and
mid-micromolar range. Recent studies using isothermal fluorescence
titration show that IL-8 as a monomer binds to heparan sulfate with a
Kd below 5 nM whereas the
Kd of dimeric IL-8 is in the mid-micromolar
range.16 Thus, the strength of the interaction can depend
on the oligomerization state of the chemokine. In addition to GAGs,
other negatively charged glycans containing sialic acid and mannose
have recently been reported to bind the chemokine
RANTES.17
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Functional aspects of GAG-chemokine interactions |
There is an increasing body of evidence suggesting that GAGs bind
and present chemokines. For example, MIP-1
, when immobilized to
proteoglycans, induces T-cell adhesion to integrin
ligands.18 IL-8 and RANTES bind to heparan sulfate in the
extracellular matrix, and these bound chemokines are then capable of
stimulating leukocyte adhesion and transendothelial
migration.19-21 In the case of MCP-1, the importance of
chemokine interaction with cell-surface GAGs for transcellular
migration was demonstrated by the almost complete absence of leukocyte
chemotaxis across monolayers of GAG-deficient mutant
cells.22 Further studies have shown that GAGs on the endothelial cell surface immobilize and enhance local concentrations of
chemokines, promoting the presentation of these cytokines to their G
protein-coupled signaling receptors.14,23 In addition, the interaction allows for the formation of immobilized gradients (haptotactic gradients) to direct the migration of the leukocyte from
the blood out into the tissue.24 Recently it was shown that heparan sulfate or heparin prevents IL-8 from unfolding, thereby
indicating a role for GAGs in IL-8 stability.16 It was postulated that in vivo this could result in prolonged IL-8 activity and preventing chemokine proteolytic degradation.
Whereas chemokines immobilized to GAGs show enhanced biological
activity, the converse is true for soluble chemokine-GAG complexes. Soluble GAGs inhibit the binding of chemokines to cell membranes containing the chemokine receptors CXCR1, CXCR2, and CCR1 and inhibit
chemokine-induced calcium flux in neutrophils.14
For the chemokine MIP-1, chemotaxis assays have shown that GAG
interaction is not an absolute requirement for functional interaction
of the chemokine with its receptor.25,26 Other work,
however, has shown that cell-surface GAGs enhance the activity of low concentrations of MIP-1 and MIP-1
by a mechanism that appears to involve sequestration onto the cell surface.27
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Molecular structures involved in chemokine-GAG interactions |
For several chemokines, such as IL-8, PF4, SDF, and MCP-1, the
C-terminal -helix is a major region involved in binding
GAGs.28-32 This has been shown by the use of C-terminal
truncations and mutagenesis of basic residues, leading to the reduction
of chemokine binding to heparin. Interestingly, a C-terminal truncation
of IL-8 exhibits reduced transcytosis and presentation by endothelial
cells in skin, suggesting a role for GAGs in these
mechanisms.10 The basic residues in the loop structures
away from the C-terminal helices of SDF-1, PF4, and RANTES are also
involved in binding GAGs.33-35 In addition, a recent
report suggests an involvement of the N terminus of
RANTES.17 MIP-1 binds GAGs, despite being an acidic
molecule, and the heparin-binding site localizes to 2 or 3 basic
residues in the loops outside the C-terminal
-helix.25,36
In the case of IL-8, PF4, SDF-1, and MCP-1, the GAG-binding
site is spatially distinct from the residues that interact with the
signaling receptor on the leukocyte. This would support a presentation
mechanism in which the chemokines bound to endothelial GAGs would be
available for interaction with receptors on the leukocyte cell surface.
An exception is MIP-1 since its GAG-binding site is the same as that
required for binding to its signaling receptor.25
There have been some studies on the GAG sequences that are involved in
chemokine binding. A specific domain of heparan sulfate that binds IL-8
has been found; the domain consists of a block that is approximately 6 monosaccharides in length.37 These blocks are
N-sulfated and may be separated by unsulfated sequences of up to about 14 monosaccharides. IL-8 binding was reported to correlate with the occurrence of the di-O-sulfated disaccharide
IdceA(2-OSO3)-GlcNSO3(6-OSO3). SDF-1 also binds to a heparan sulfate sequence consisting of 6 monosaccharides in length, and PF4 binds to a 9-kDa fragment of the GAG
that is enriched in N-sulfated disaccharides and iduronate 2-O-sulfate residues.34,38 Thus, the structure
and spacing of the sulfated domains are important variables in
GAG-chemokine interactions.
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Selective binding of chemokines to GAGs |
Chemokines exhibit wide variation in their affinity for heparin,
with the order as follows: RANTES, MCP-1, IL-8, MIP-1. The weaker binding of MIP-1 relates to its overall negative charge, contrasting with other chemokines, which are highly
basic.14 Chemokines show selectivity in their strength of
interaction with GAGs. For RANTES, the order is heparin, dermatan
sulfate, heparan sulfate, chondroitin sulfate whereas for MCP-1
and IL-8 the order is heparin, heparan sulfate, chondroitin sulfate or
dermatan sulfate (in this last listing, the final 2, chondroitin
sulfate and dermatan sulfate, are equivalent). These
differences can in part be explained by the negative charge density of
the GAG, but cannot be completely explained by this since dermatan
sulfate and chondroitin sulfate have similar levels of sulfation;
however, RANTES shows far higher affinity to the former GAG than the
latter. Further evidence of selective binding has come from
affinity coelectrophoresis experiments.39 IL-8 and GRO
were shown to bind preferentially to a fraction of heparin, whereas PF4
or NAP-2 did not show the same binding preference. Furthermore,
selectivity is apparent at the cell surface. IP-10 binds to a specific
and saturable cell-surface heparan sulfate-binding site on endothelial
and other cells.40 This site is shared with PF4 but not
with IL-8, MCP-1, RANTES, MIP-1, or
MIP-1.
Heparan sulfate is highly heterogeneous in structure, and endothelial
cells have the capacity to express this molecule on their cell surfaces
with subtle variations among different vascular beds. For example,
porcine endothelial cells from veins and arteries have been shown to
synthesize heparan sulfate chains that differ in charge density and
sulfation pattern.41 Although there were no differences in
size or chain length, heparan sulfate from aorta was more highly
charged, with increased sulfation and more clustering of N-sulfated
portions of the chains. In the microvasculature of human skin and
synovium where leukocyte transmigration occurs, chemokine-binding sites
are expressed only on venular endothelial cells, not on
arterioles, suggesting that chemokine-binding motifs on heparan
sulfate may be differentially expressed in these 2 vascular
sites.8,10 Recent evidence shows that there are
differences in the sulfation patterns of heparan sulfate from human
bone marrow and human umbilical vein endothelial cells. There was more
O-sulfation of the N-sulfated domains in heparan
sulfate from the endothelial cells of bone marrow compared with those
from umbilical veins.42 Binding experiments showed that
bone marrow endothelial cells bound more SDF-1 per cell than human
umbilical vein endothelial cells, and binding was inhibited by
O-sulfated heparin and less by N-sulfated
heparin. Therefore, it was postulated that highly sulfated domains in
heparan sulfate from bone marrow endothelial cells contribute to tissue
specificity where endothelial cells present SDF-1 to hematopoietic
progenitor cells, resulting in their transmigration. Little is known
about the control mechanisms that lead to the regulated diversity of
heparan sulfate structures expressed in different cells and tissues.
One reason may be the selective expression of isoforms of enzymes
involved in heparan sulfate synthesis. Most tissues express
N-deacetylase/N-sulfotransferase-1 (NDST-1) and
NDST-2, whereas heparin-producing mast cells show a predominance of
NDST-2.43 It remains to be found out if the expression of
such enzyme isoforms varies between endothelial cells in different
vascular beds.
Although the main GAG expressed by endothelial cells is heparan
sulfate, these cells also express chondroitin and dermatan sulfate, and
the proportions of these GAGs can change between different endothelial
cells. For example, human aortic endothelial cells synthesize mainly
heparan sulfate with small amounts of chondroitin
sulfate.44,45 Human umbilical vein endothelial cells also
produce mainly heparan sulfate, but they also synthesize more
chondroitin and dermatan sulfate than aortic endothelial cells.46 In addition, the major GAG in basement membranes
is heparan sulfate. However, this can vary since mouse bone marrow venous sinusoids show unusually abundant chondroitin sulfate
proteoglycan and an absence of heparan sulfate
proteoglycan.47
Altered expression in the type of blood vessel GAG has been observed in
several pathological and physiological situations, such as
atherosclerosis, inflammatory bowel disease, and wound healing.48,49 For example, in the intima of
atherosclerotic human aortas, there is a decrease in the proportion of
heparan sulfate and an increase in the proportions of chondoitin and
dermatan sulfate, which are produced by smooth muscle
cells.44,50 These changes in GAG composition occur in the
extracellular matrix of the blood vessel wall and could alter the
nature of haptotactic chemokine gradients, thereby influencing
leukocyte migration into the tissue.
In summary, endothelial cells demonstrate flexibility in terms of the
expression of the type of GAG and the fine structure of their
carbohydrate chains in different tissues. Variations in GAG
carbohydrate sequences and positioning of negatively charged groups,
together with amino acid sequence differences among chemokines, contribute to the selectivity of the chemokine-GAG interactions. This
raises the intriguing possibility that GAG substructures at the
endothelial cell surface participate in determining the types of
chemokines transcytosed and presented in a given inflammatory site and
hence lend selectivity to the types or subsets of leukocytes recruited.
Furthermore, differential expression of GAGs in the extracellular
matrix of the blood vessel wall could modify chemokine gradients and
further influence leukocyte migration.
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The Duffy antigen/receptor for chemokines (DARC) |
This protein was originally described on red blood cells and is
the site where the malaria parasite, Plasmodium vivax,
invades erythrocytes. The protein also occurs on several other cell
types, including the endothelial cells of postcapillary venules in
kidney, lung, thyroid, and spleen, but not on the endothelial cells of arterioles and arteries.51,52 Thus, there is selectivity
in DARC expression between endothelial cells, occurring in the segment of the circulation where leukocyte extravasation takes place.
DARC has a serpentine structure with 7 transmembrane domains, like
other chemokine receptors, yet is not G protein coupled and has no
known signaling mechanism.53 It exhibits broad
specificity, binding members of both CC and CXC classes of chemokines,
except MIP-1 and MIP-1, and the C-chemokine
lymphotactin.54,55 IL-8, MGSA, RANTES, and MCP-1 show
high-affinity binding to DARC, with a Kd of
approximately 5 nM.54,56 Binding studies in inflamed and
normal human tissues have shown that DARC expressed by the venular
endothelium binds chemokines in situ.8,9 This has been
shown by using blocking antibodies to DARC and by the demonstration that the chemokine-binding profile to venules is similar to that of
DARC since IL-8 binding can be displaced by excess RANTES, indicating a
multispecific site, and there is lack of MIP-1
binding.8,9
The function of DARC is yet to be fully defined. However, recent
gene-deletion studies in mice suggest that the protein has a functional
role in inflammation since these animals show altered leukocyte
recruitment compared with wild type when given the inflammatory stimuli
lipopolysaccharide (LPS) and thioglycollate, yet in all other respects
they are normal.57,58 DARC may function in chemokine endocytosis/transcytosis in endothelial cells. This hypothesis is based
on the observations that endothelial DARC localizes to caveolae,51 which are associated with vesicular transport.
In addition, use of DARC transfectants shows that the protein binds and
internalizes chemokines.56 When IL-8 or RANTES is injected into the skin, these chemokines localize to caveolae of endothelial cells, where they are transported to the luminal surface and
presented.10 Since DARC also localizes to endothelial
caveolae, these data further suggest a role for the protein in
chemokine transcytosis. The DARC-binding region of the chemokine MGSA
is different from that involved in the interaction with
CXCR2.59 This finding, together with the observation that
DARC occurs at the endothelial cell surface,51 implies
that the protein could potentially act as a chemokine-presenting
molecule. However, there is evidence that chemokines bound to DARC on
the red blood cell surface do not activate neutrophils in terms of
calcium flux.60 Therefore, other molecules, such as
GAGs, may be more important in presentation. Further functions have
been proposed for DARC. It could act as a decoy receptor or as a
signal-transducing receptor with an, as yet, unknown signaling
mechanism.52,60,61 Thus, in summary, DARC could
potentially act as chemokine transporter although further work is
required to clarify its function in the endothelium.
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G protein-coupled chemokine receptors |
Cultured endothelial cells have been shown to express a variety of
G protein-coupled signaling chemokine receptors, including CCR2 and
CCR8 and CXCR1, CXCR2, CXCR3, and CXCR4,62-66 although the
expression of endothelial CXCR1, CXCR2, and CXCR3 in vitro is variable
depending on the cell source and culture
conditions.10,67-69 In addition, the in situ expression of
CXCR2 and CCR2 has been shown on endothelial cells in human skin and
inflamed tissue.63,70
The expression of these chemokine receptors on endothelial cells leads
to signal transduction and biological responses. Such responses include
shape changes, cytoskeletal rearrangements, and cell division. Some
chemokines are angiogenic (eg, IL-8, MCP-1, and I-309) and others
angiostatic (eg, IP-10 and MIG), and activation of their respective
chemokine receptors results in the stimulation or inhibition of
endothelial cell proliferation and chemotaxis. Other endothelial
responses to chemokines include IL-8-stimulated increase in vascular
permeability in vitro and in vivo and edema formation in
vivo.71-73
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Topographical distribution of chemokines, chemokine receptors, and
adhesion molecules on endothelial cells and leukocytes |
The surfaces of endothelial cells and leukocytes are not smooth,
but contain numerous microvillous processes. These projections have
been shown to harbor the preferential distribution of certain adhesion
molecules, chemokines, and chemokine receptors, and this distribution
may be functionally important in leukocyte extravasation, as has
especially been shown for selectin adhesion molecules.
On the surface of leukocytes, immunoelectron microscopic studies have
shown that L-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), and
the integrins 47 and 41 are concentrated on microvilli.74-79 Eighty percent of PSGL-1 label is
localized to the tips of neutrophil microvilli.79
L-selectin, PSGL-1, and 47 and 41 integrins, together with
their counterligands, can mediate the formation of initial cell
contacts between the leukocyte and the endothelium (termed tethering)
and subsequent rolling. Less is known about the distribution of
counterligands for leukocyte adhesion molecules on the endothelial cell
surface. MECA-79, an antibody that recognizes the
counterligands for L-selectin, localizes to the microvilli of
endothelial cells.80 Similarly, the sialomucin CD34, one
of the counterligands for L-selectin, is concentrated on endothelial
microvilli.81,82
The functional significance of the microvillous distribution of
molecules involved in leukocyte extravasation has been shown for
L-selectin. Von Andrian et al 83 constructed chimeras
containing the transmembrane and intracellular domains of CD44 and
the functional extracellular domain of L-selectin. This chimera
targeted the extracellular domain of L-selectin away from leukocyte
microvilli to the planar cell body. When intact L-selectin was used, it
localized to microvilli and dramatically mediated initial contact
formation of leukocytes to its ligand under flow. However, the chimera
exhibited little ability to initiate tethering to its ligand. These
studies have been confirmed in vivo by means of intravital microscopy, which showed that microvillous expression of the L-selectin ectodomain is important for leukocyte tethering in peripheral lymph
nodes.84 In another study, Finger et al85
demonstrated that disruption of leukocyte microvilli using cytochalasin
B or hypotonic swelling can result in nearly complete inhibition of
tethering. Taken together, these studies show that presentation of
L-selectin by microvilli is functionally important in the earliest part
of the adhesion cascade.
At the luminal cell surface of the endothelium, chemokines are
presented to blood leukocytes during the early stages of
endothelial-leukocyte interactions.10 Using immunoelectron
microscopy, we found that the chemokine IL-8 is preferentially
distributed on the microvillous processess of endothelial cells where
immunoreactivity is 10 times higher than on the planar cell surface,
and 2 out of 3 microvilli harbor the chemokine. This suggests that the
chemokine-binding sites, such as GAGs and potentially DARC, are
concentrated on these endothelial protrusions. Interestingly, the
chemokine receptors CCR2, CCR5, and CXCR4 occur predominantly on the
microvilli of macrophages and T cells.86 Thus, the
microvillous localization of chemokines and their receptors may be
spatially important during the activation stage of leukocyte emigration.
During the subsequent arrest and firm adhesion of the leukocyte, a role
for microvilli is less implicated. The 2 integrins are excluded from
leukocyte microvilli but are distributed on the planar cell
surface.75,76,83,87 These molecules cannot initiate
cell-cell contact under physiological flow 88 but are specialized for firm leukocyte adhesion to the endothelial cell surface, once they have been activated by chemokines.89,90 Recruitment to the planar cell body may ensure this later role of 2
integrins in the multistep adhesion process by precluding its
availability at sites of initial contact. The distribution of the
integrin ligands intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the
endothelial cell membrane has been shown in mice.91 ICAM-1
occurs both on the smooth surface of the plasma membrane and on
microvilli, and VCAM-1 shows a uniform distribution on the smooth
surface of the endothelium. On cultured human dermal endothelial cells,
ICAM-1 has been shown to localize to microvillous cell
protrusions.92
One reason for the preferential distribution of chemokines, chemokine
receptors, and certain adhesion molecules on microvilli is that these
structures may be the first points of contact between blood leukocytes
and the endothelium, and thus are spatially the most effective site to
cluster ligand and receptor pairs. Another reason relates to the
glycocalyx. This negatively charged structure, which coats leukocytes
and endothelial cells,93,94 could create electrostatic
repulsion between the 2 cell types and inhibit cell contact. In
the presence of microvilli, the surface area making contact is limited
to the outermost cell periphery, where electrostatic repulsion would be
least, thereby creating a contact-promoting environment.83
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The model |
In consideration of some recent ultrastructural reports and the
data presented in the previous sections, the current model of
chemokine-driven leukocyte transmigration can be extended (Figure 1).
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| Figure 1.
Subcellular events in the endothelium during
chemokine-directed leukocyte extravasation.
(A) Noninflamed tissue. (B) Inflamed tissue. Release of chemokines from
extravascular cells in the tissue occurs ( ), and there is
wrinkling of the endothelial cell surface. Chemokines are taken up at
the abluminal surface of the endothelium and transcytosed in caveolae.
This process involves binding to glycosaminoglycans (GAGs)
and/or the Duffy receptor. At the luminal surface, chemokines are
released and bound preferentially on the tips of projections. These
mediators may also be produced and released directly by endothelial
cells, in which case they are also bound at the luminal surface but not
transcytosed (- - ->). (C) Chemokines bound at the luminal
endothelial cell surface build up in concentration. They do this
sufficiently to bind to and activate the signaling receptors on the
leukocyte cell surface, leading to activation of integrins and firm
attachment. (D) Leukocyte migration occurs either transcellularly
through a pore in the endothelial cell or through the intercellular
junction, following a chemokine gradient bound to GAGs and/or the Duffy
receptor. The cell then enters the basement membrane and continues
migration along a chemokine gradient that is soluble or immobilized to
the extracellular matrix.
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One of the earliest ultrastructural changes that occurs when a
chemoattractant N-formyl-methionyl-leucyl-phenylalanine
(FMLP) or chemokine (IL-8) is injected into the skin is
wrinkling of the endothelial plasma membrane, increasing the number of
cell-surface projections.1,95,96 This activation occurs as
early as 5 minutes after injection and before neutrophil margination
and transmigration. The cellular mechanisms causing this wrinkling are
not known but could be mediated by chemoattractant receptors and
cytoskeletal changes. IL-8 can be detected in the endothelium by
immunoelectron microscopy and electron microscopic autoradiography at
the abluminal surface, intracellularly, and at the luminal surface.10 The amount of endothelial IL-8 builds up with
time from 0 to 120 minutes, with most neutrophil transmigration
occurring at 60 and 120 minutes. The chemokine reaches the luminal
endothelial surface by abluminal-to-luminal transcytosis, traversing
the cell in caveolae. These subcellular structures have been envisaged as forming discrete vesicles that shuttle across the cell or
interconnected clusters of vesicles and vacuoles that form
transendothelial pores (the vesiculo-vacuolar
organelles).97,98 Following fusion of the caveolae with
the membrane at the luminal surface, chemokines are preferentially
presented on the tips of endothelial projections, creating the spatial
organization to maximize the presentation of chemokines in the rolling
phase of leukocyte emigration. The buildup of chemokine at the luminal
surface of the endothelium is proposed to occur by chemokine
immobilization mediated by interactions with cell surface
GAG.14 The chemokines interact with the G protein-coupled
chemokine receptors on the leukocyte cell surface, resulting in
activation of integrins and firm attachment to the endothelium.
Following firm attachment, the leukocyte migrates from the blood
across the endothelial barrier. Two possibilities exist concerning the
route of migration: transcellular migration across the endothelium or
intercellular movement through open junctions between endothelial cells. When FMLP is injected into the guinea pig skin, examination of
serial sections by electron microscopy and computer-assisted 3-dimensional reconstruction shows that neutrophils follow the transendothelial route, unrelated to interendothelial
junctions.96,99 Earlier studies have also suggested that
neutrophils, monocytes, and eosinophils migrate transcellularly in
response to the mediators IL-8, NAP, IL-1, C5a, leukotriene B4
(LTB4), and other inflammatory stimuli, but were incapable
of proving this because serial sections were not used to generate
3-dimensional information.95,100-102 Other in vivo studies
employing serial sections and electron microscopy have indicated that
leukocytes can take the intercellular pathway of
extravasation.103,104 Therefore, it is probable that
leukocytes can take the transcellular or intercellular migratory route,
the exact pathway depending on factors such as the type of leukocyte, inflammatory stimulus, tissue, and animal. The in vitro route of
leukocyte transmigraton across the endothelium is more clear, with
intercellular traffic through endothelial junctions being the accepted
mechanism.105
When IL-8 is administered in rabbit and human skin, electron
microscopic examination reveals neutrophil extravasation consistent with the transcellular path.95 Over the time course of
neutrophil recruitment, the injected IL-8 localizes to caveolae and
larger vesicles in the endothelial cytoplasm, which increase in
abundance following chemokine administration.10,106 The
intercellular junctions are ultrastructurally intact, and no IL-8 label
is associated with these structures. Thus, both the transport of IL-8
and the leukocyte migration are transcellular. The former occurs in an abluminal-to-luminal direction and the latter in a luminal-to-abluminal direction. Thus, chemokine bound to GAG or DARC would provide a
haptotactic transcellular gradient giving the leukocyte the directional
cue to take the transcellular route. When adherent neutrophils migrate
transcellularly, they extend projections (pseudopods) into the
endothelial cell and then migrate through endothelial pores.96 During this process, it is likely that they
encounter immobilized chemokines, which would give them further
directional information. Once through the endothelium, the leukocytes
encounter further chemokine, in immobilized or soluble form, in the
extracellular matrix and on the surface of pericytes, giving them cues
to cross the blood vessel wall and move out into the extravascular
space.10,95
| |
Acknowledgments |
The views expressed in this publication are those of the authors.
| |
Footnotes |
Submitted November 1, 2001; accepted July 24, 2002.
Supported by funding from the Arthritis Research Campaign,
Smiths' Charity, Wellcome Trust, Droitwich Medical Trust, and
Institute of Orthopaedics, Robert Jones and Agnes Hunt Orthopaedic
Hospital, United Kingdom. This work was undertaken by the Robert Jones
and Agnes Hunt Orthopaedic and District Hospital National Health
Service (NHS) Trust, which receives a portion of its funding
from the NHS Executive.
Reprints: Jim Middleton, Endocube, Laboratoire de
Biologie Vasculaire-IPBS-CNRS, 205 route de Narbonne, 31077 Toulouse,
France; e-mail: jim.middleton{at}ipbs.fr.
| |
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Abstract
Introduction
