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*
Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; and
Department of Immunology, Duke University Medical Center, Durham, NC 27710
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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300 cells/min/venule) in wild-type mice at
4–24 h. This response was reduced by approximately 60–70% in
L-selectin-deficient mice and in wild-type mice treated with an
L-selectin-blocking mAb. P-selectin blockade by Ab completely inhibited
leukocyte rolling at 4–24 h in wild-type animals and also blocked the
residual rolling seen in L-selectin-deficient mice. Blocking E-selectin
function had no effect on leukocyte rolling flux at any time point in
wild-type or L-selectin-deficient mice. Despite reduced rolling,
leukocyte adhesion and emigration were not measurably reduced in the
L-selectin-deficient mice in this vascular bed. In conclusion,
leukocyte rolling is L-selectin-dependent post-Ag challenge with
L-selectin and P-selectin sharing overlapping
functions. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L-selectin, which is constitutively expressed on most leukocytes, is involved in lymphocyte recirculation 6 and leukocyte-endothelial cell interactions at peripheral sites of inflammation 7, 8 . For example, leukocyte infiltration into the inflamed peritoneum is significantly reduced by i.v. administration of a mAb or soluble recombinant L-selectin 7, 8 . In addition, L-selectin blockade by Abs provides partial protection from acute inflammation in the heart, lung, and other organs 9, 10, 11 . L-selectin-deficient mice show a significant impairment in migration to the inflamed peritoneum, to nonspecific skin irritants, as well as resistance to LPS-induced septic shock 12, 13, 14 . Additionally, these mice have an impairment in contact hypersensitivity responses to reactive haptens 12 , an observation confirmed by others 14, 15 . Whether the observed reduction in hapten-induced inflammation is due to early events in Ag sensitization or more delayed effector mechanisms remains unclear. Catalina et al. proposed that the defect resides in the inability of Ag-specific T cells to home to and be activated in peripheral lymph nodes and that T cell, neutrophil, and monocyte effector populations were able to enter inflamed skin sites from the peripheral vasculature regardless of the presence or the absence of L-selectin 14 . Others 15 have noted an impairment in leukocyte recruitment in response to Ag within the first 4 days of sensitization in L-selectin-deficient mice but not after 9 days of sensitization and interpreted these results to suggest an impairment in T cell priming rather than an impairment in Ag-driven leukocyte recruitment in the peripheral microvasculature. Still other work suggests that the immunization phase is not impaired in L-selectin-deficient mice. Although, humoral immune responses in L-selectin-deficient mice following peripheral challenge are slightly delayed, they are generally higher than responses in wild-type littermates 16 . Similarly, the generation of effector cytotoxic T cells in response to allogeneic skin transplants is normal, if not enhanced, in L-selectin-deficient mice 17 .
The aforementioned studies raise important questions about the effector phase of Ag responses and whether the absence of L-selectin alters the leukocyte recruitment pathway in response to Ag in the peripheral microvasculature. In this study we immunized mice, challenged them locally with Ag 14 days later, and visualized the immune responses in the microvasculature of mice lacking L-selectin function. Since function-blocking anti-L-selectin mAbs can affect leukocyte function as well as influence rolling 18, 19 , a multitiered study was conducted using both L-selectin-deficient mice and an L-selectin Ab to inhibit L-selectin function in wild-type mice. The first objective of this study was to directly and systematically elucidate the role of L-selectin at various stages of Ag-induced leukocyte recruitment in a peripheral microvascular bed. Although previous work has shown a role for P-selectin at an early time in this model, this does not preclude a role for L-selectin, since L- and P-selectin have overlapping functions 20, 21, 22 . Moreover, the possibility that L-selectin plays an exclusive role later in the development of Ag-induced immune response cannot be dismissed. Therefore, the second objective of this study was to examine whether L-selectin-dependent rolling overlapped with or was distinct from that of the endothelial selectins.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice deficient in L-selectin were generated by gene targeting in embryonic stem cells as previously described 12, 13 and were backcrossed with C57BL/6 mice for seven generations. Wild-type C57BL/6 mice (Charles River Laboratories, Wilmington, MA) were used as controls. All mice weighed between 20–35 g and were between 6–10 wk of age at the time of use. One postcapillary venule was visualized per mouse, therefore, n refers to the total number of mice and/or venules examined.
Immunization protocol
Mice were systemically (i.p.) sensitized with 10 µg of chicken egg OVA mixed with 10 mg of grade V aluminum hydroxide (both from Sigma, St. Louis, MO) in a total volume of 0.2 ml of saline. Two weeks later, mice were challenged locally (intrascrotal injection) with the sensitizing Ag (10 µg in 10 mg of AlOH). The animals were prepared for intravital microscopy, and leukocyte-endothelial cell interactions were examined during the late phase response, at 4, 8, or 24 h after saline or OVA challenge. Sham sensitization and/or sham challenge involved injection of AlOH alone. This regimen does not elicit leukocyte recruitment as described previously 23 . As an additional control, to examine whether an irrelevant Ag would induce leukocyte rolling, OVA-sensitized animals were challenged with AlOH plus BSA. In these experiments BSA did not induce an increase in leukocyte rolling (data not shown), suggesting that our model did indeed induce Ag-specific inflammation.
Intravital microscopy
Mice were anesthetized by i.p. injection with a mixture of 10 mg/kg Xylazine (MTC Pharmaceuticals, Cambridge, Canada) and 200 mg/kg ketamine hydrochloride (Rogar/STB, Montreal, Canada). The left jugular vein was cannulated to administer anesthetic and drugs. An incision was made in the scrotal skin to expose the left cremaster muscle, which was then carefully removed from the associated fascia. A lengthwise incision was made on the ventral surface of the cremaster muscle. The testicle and epididymis were separated from the underlying muscle and placed into the abdominal cavity. The muscle was then spread out over an optically clear viewing pedestal and secured along the edges with 5–0 suture. The exposed tissue was suffused with bicarbonate-buffered saline (pH 7.4, 37°C). The cremasteric microcirculation was observed through an intravital microscope (Optiphot-2, Nikon, Tokyo, Japan) with a x25 objective lens (Leitz Wetzlar L25/0.35) and a x10 eyepiece. The image of the microcirculatory bed (x1400 magnification on the video monitor) was recorded using a video camera (Panasonic-Digital 5100, Secaucus, NJ) and a video recorder (Panasonic NV8950) as previously described 20, 23 . Images of the microcirculation were recorded over a 30-min time frame.
A single unbranched cremasteric venule (20–40 µm in diameter) was
selected in each mouse for study. Venular diameter (Dv) was
measured using a video caliper (Microcirculation Research Institute,
Texas A & M University, College Station, TX). Rolling leukocytes were
defined as those leukocytes that rolled at a velocity slower than that
of RBC. Leukocyte rolling velocity was measured for the first 20
leukocytes entering the field of view at 0, 15, and 30 min and
determined as the time required for a leukocyte to traverse a given
length of venule. Leukocyte adhesion was quantified as the number of
leukocytes that adhered to the vessel wall for 30 s or more within
the same area of vessel throughout the experiment. The number of
emigrated leukocytes was quantified by counting cells in the
extravascular space within the field of view (a region of 200
x 300 µm) adjacent to the venule under study. RBC velocity
(Vrbc) was measured on-line using an optical Doppler
velocimeter (Microcirculation Research Institute). Venular blood
flow was calculated from the product of cross-sectional area and mean
RBC velocity (Vmean = Vrbc/1.6), assuming
cylindrical geometry. Venular wall shear rate (
) was calculated
based on the Newtonian definition: =
8(Vmean/Dv) 24 .
Experimental protocol
Leukocyte kinetics were examined over a 30-min period in wild-type mice and in sensitized wild-type mice at 4, 8, and 24 h post-Ag challenge. Identical protocols were conducted in L-selectin-deficient mice and in sensitized wild-type mice that received anti-L-selectin mAb (MEL-14; 100 µg/animal i.v.; PharMingen, Mississauga, Canada). The MEL-14 mAb concentration used was the maximum amount that did not induce leukocytopenia, in agreement with that reported by numerous laboratories 13, 25 . In some experiments wild-type and L-selectin-deficient mice received an anti-P-selectin Ab (RB40.34; 20 µg/animal iv; PharMingen, San Diego, CA) or an anti-E-selectin Ab (9A9; 100 µg/animal i.v.; Dr. Barry Wolitzky, Hoffmann-La Roche, Nutley, NJ) administered at 5 min of the experimental protocol. These were the mAb concentrations required to inhibit all P-selectin- and E-selectin-dependent leukocyte rolling as previously described 23 .
At the end of each experiment, whole blood was drawn via cardiac puncture. Total leukocyte counts were performed using a Bright-line hemocytometer (Hausser Scientific, Horsham, PA) in all groups of mice.
Passive cutaneous anaphylaxis reaction
Blood was obtained from all OVA-sensitized animals at the end of the experiment by intracardiac puncture to generate serum. Serial dilutions (1/8 to 1/64) of the serum samples were prepared, and 200 µl of each sample was injected intradermally into the shaved backs of untreated Sprague-Dawley rats. Seventy-two hours later the rats were challenged systemically with a solution of 5 mg of chicken OVA in 1.5 ml of saline containing 2.5 mg of Evan’s Blue dye. Sixty minutes later the highest dilution that produced a distinct blue region (Evan’s Blue dye leakage) at the center of the injection site was read as the Ab titer 26 . Animals were considered sensitized only if they had serum anti-OVA antibody titers of at least 1/64 as previously reported 23 . Sham-sensitized animals had no detectable anti-OVA antibodies.
Statistical analysis
Data are presented as the mean ± SEM. Student’s t test with Bonferroni correction was used for multiple comparisons. Statistical significance was set at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Venular diameters, RBC velocities, and shear rates were similar in
examined vessels of untreated and MEL-14 mAb-treated wild-type mice and
L-selectin-deficient mice (Table I
).
Administration of the L-selectin blocking Ab in wild-type mice had no
effect on circulating leukocyte counts. Concentrations of MEL-14 higher
than that used in this study (100 µg/mouse) do cause leukocytopenia.
All mice used in these studies appeared healthy and showed no visual or
serologic signs of infection. Hemodynamic parameters, including venular
diameter, RBC velocity, and calculated wall shear rates remained
relatively constant in all animals in all preparations for the 30-min
duration and were not affected by Ag sensitization and challenge (data
not shown). All mice immunized with chicken egg OVA had serum
anti-OVA titers of at least 1/64 as measured by a passive cutaneous
anaphylaxis reaction.
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Leukocyte rolling in untreated animals
Approximately 60 cells were rolling per minute in single
cremasteric venules of L-selectin-deficient mice and their wild-type
counterparts (Fig. 1A).
Administration of the MEL-14 Ab to wild-type mice after 5 min did not
significantly affect leukocyte rolling flux (Fig. 1A).
Leukocytes rolled at velocities of approximately 40–50 µm/s in
wild-type mice, and treatment with the MEL-14 Ab did not significantly
reduce the average rolling velocity (Fig. 1B). However,
rolling velocities were significantly slower in L-selectin-deficient
mice (20 µm/s or less). The reason for this is not entirely clear;
however, it is conceivable that the rolling population of leukocytes
may be different between control wild-type and control
L-selectin-deficient mice. The rolling velocity differences between the
MEL-14 mAb-treated wild-type mice and L-selectin-deficient mice
suggests that MEL-14 mAb only partially neutralizes L-selectin
function under these conditions. Minimal amounts of adhesion (<5
cells/100 µm length of venule) and emigration (<5 cells/field of
view) were noted following cremaster exteriorization in all three
groups of mice, suggesting that all tissues had minimal amounts of
inflammatory infiltrate under basal conditions (data not shown).
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Ag challenge induced a significant increase in the flux of
leukocyte rolling within cremaster venules of wild-type mice. Leukocyte
rolling flux in wild-type mice was elevated from control levels (60
cells/min/venule) to as much as 300 cells/min/venule at 4–24 h
following Ag challenge (Fig. 2,
A–C). In striking contrast, Ag challenge failed to increase
the leukocyte rolling flux in L-selectin-deficient mice for up to
24 h (Fig. 2, A–C). In fact, leukocyte rolling flux in
L-selectin-deficient mice consistently remained between 50 and 60
cells/min/venule, significantly below the values observed in wild-type
mice.
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50 µm/s; Fig. 2
, D and E), although there
was a significant 40% decrease in leukocyte rolling velocity by
24 h (30 µm/s; Fig. 2F). By contrast, rolling
velocities were always significantly lower (<20 µm/s;
p < 0.05) in L-selectin-deficient mice and were as low
as 10 µm/s by 24 h (Fig. 2, D–F). These results
indicate that Ag challenge in wild-type mice induces leukocyte
recruitment through L-selectin-dependent pathways, with the cells
exhibiting the faster rolling velocities characteristic of L-selectin
function. L-selectin blockade reduces Ag-induced leukocyte rolling
To verify that Ag challenge in wild-type mice induced leukocyte
recruitment through L-selectin-dependent pathways, wild-type mice were
treated with anti-L-selectin function-blocking mAb following Ag
challenge. Ag challenge in wild-type mice induced significant leukocyte
rolling flux by 4 h (250 cells/min/venule; Fig. 3A). Treatment of these mice
with the anti-L-selectin Ab significantly attenuated leukocyte
rolling flux by >60% within seconds of administration (75 cells/min;
p < 0.05; Fig. 3A). Anti-L-selectin mAb
treatment produced a very similar inhibitory response at 8 h (Fig. 3B) and at 24 h post-Ag challenge (Fig. 3C)
in OVA-sensitized wild-type mice. An isotype-matched control Ab
does not reduce leukocyte rolling in this model of inflammation 12 .
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D). The impact of L-selectin blockade on leukocyte
rolling velocity was significant by 8 h post-Ag challenge (40%
decreased; p < 0.05; Fig. 3E). Treatment
with MEL-14 mAb did not significantly reduce leukocyte rolling
velocities in mice 24 h after Ag exposure (Fig. 3F).
However, leukocyte rolling velocities were already significantly
reduced in Ag-treated mice with and without mAb by 24 h (Fig. 3F) relative to rolling velocities in wild-type mice that
were not challenged with Ag (Fig. 1B). MEL-14 mAb-treated
wild-type mice (Fig. 3, D–F) had faster rolling velocities
than L-selectin-deficient mice at comparable time points following Ag
challenge (Fig. 2, D–F). This probably reflects incomplete
inhibition of L-selectin function by treatment with the MEL-14 mAb;
however, higher concentrations of MEL-14 Ab cause leukocytopenia.
Nonetheless, the decreases in leukocyte rolling flux and rolling
velocities following L-selectin blockade (Fig. 3) are similar to the
results obtained in L-selectin-deficient mice (Fig. 2). Blocking P-selectin and E-selectin function
Since 25–40% of leukocyte rolling remained in the
L-selectin-deficient mice after Ag challenge, a role for either
E-selectin or P-selectin was examined (Fig. 4). Blocking P-selectin function in
L-selectin-deficient mice completely blocked leukocyte rolling at 4, 8,
and 24 h post-Ag challenge (Fig. 4, A–C). By contrast,
blocking E-selectin function did not affect leukocyte rolling flux in
the L-selectin-deficient mice at 4, 8, or 24 h after Ag challenge
(Fig. 4, D–F). Also, blocking E-selectin function had no
effect on leukocyte rolling velocity at any of the time points examined
(data not shown). In untreated L-selectin-deficient mice (no Ag),
blocking P-selectin function, but not E-selectin function, prevented
all leukocyte rolling (data not shown).
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)
completely inhibited both the P-selectin- and L-selectin-dependent
Ag-induced leukocyte rolling. Inhibition of E-selectin function had no
effect on either rolling flux (Fig. 5) or leukocyte rolling velocity
(data not shown) at these time points. Complete inhibition of rolling
with P-selectin Ab has previously been shown at 8 h 23 but not
at 4 h or 24 h, so this time point was not repeated.
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Despite the lack of Ag-induced leukocyte rolling flux in
L-selectin-deficient mice by 4–24 h, leukocyte adhesion (Fig. 6A) and emigration (Fig. 6B) was not inhibited. In fact, leukocyte recruitment was
higher in L-selectin-deficient mice than in wild-type mice at the early
time points. There was no further increase in leukocyte emigration
after 4 h post-Ag challenge in L-selectin-deficient mice, whereas
emigration continued in wild-type mice between 8 and 24 h post-Ag
challenge. Histology revealed that emigrated leukocytes consisted of
neutrophils, eosinophils, and a small number of mononuclear cells. The
percentage of each cell type was similar in L-selectin-deficient and
wild-type mice in this model system at 24 h. It was intriguing
that there were fewer leukocytes (all types) in L-selectin-deficient
mice further away from the microvessels. Whether this reflects less
migration of L-selectin-deficient cells in extravascular space requires
further investigation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In addition,
Ag challenge did not induce leukocyte rolling in
L-selectin-deficient mice at any time point examined (Fig. 2). The
fact that L-selectin-deficient mice and the L-selectin Ab-treated
wild-type mice responded similarly in these studies suggests that
L-selectin does indeed contribute to leukocyte rolling in the
peripheral vasculature during immune responses to Ag challenge. The
current studies also demonstrate that the reduced Ag-dependent cellular
hypersensitivity responses previously observed in L-selectin-deficient
mice 12, 14, 15 may result from impaired leukocyte-endothelial cell
interactions at sites of Ag challenge, rather than decreased Ag
sensitization or the ineffective generation of effector cells. Both
wild-type and L-selectin-deficient mice generated similar titers of
anti-OVA antibodies as determined by passive cutaneous anaphylaxis
assays. Moreover, leukocyte-endothelial cell responses in wild-type
mice were significantly inhibited by blocking L-selectin function,
which resulted in responses remarkably similar to those observed in
L-selectin-deficient mice (Figs. 2 and 3). Therefore, these studies
emphasize a role for L-selectin in response to Ag-induced leukocyte
recruitment during leukocyte migration into affected tissues.
Ag-induced leukocyte rolling was also entirely inhibited by blocking
P-selectin function at 4 and even 24 h post-Ag challenge (Figs. 4 and 5). The fact that either genetic or mAb blockade of L-selectin
function profoundly inhibited Ag-induced leukocyte rolling that is also
entirely dependent on P-selectin indicates that both P-selectin and
L-selectin are required for effective leukocyte rolling in vivo in the
Ag-inflamed peripheral microvasculature. Overlapping contributions for
P-selectin and L-selectin to rolling have been demonstrated previously
in some models of acute inflammation 20, 21, 22 . However, the overlapping
roles of P-selectin and L-selectin are not always evident; during
thioglycolate-induced peritonitis, impairment of leukocyte recruitment
remains evident by 24–48 h in L-selectin-deficient mice 12 , but not
in P-selectin-deficient mice 27 . In our study, both adhesive
mechanisms contributed to leukocyte rolling in the cremasteric muscle
microvasculature over the first 24 h. In fact, significant rolling
was still detected when wild-type mice received anti-L-selectin Ab
or in L-selectin-deficient mice, and the remaining rolling was
P-selectin dependent (Figs. 4 and 5). Thus, some Ag-induced leukocyte
rolling can occur independent of L-selectin expression, but not
P-selectin expression, in the cremasteric muscle microvasculature under
the conditions of these experiments.
One possibility is that L-selectin may promote initial capture of
leukocytes from the mainstream of blood before the leukocyte rolls on
endothelial selectins. Indeed, neutrophil rolling on purified
E-selectin required L-selectin for initial capture; however, if the
neutrophils were allowed to first settle on purified E-selectin,
L-selectin was no longer required for rolling 28 . A similar
observation has been made in vivo for L-selectin and 
4
integrin in a chronic model of vasculitis 29 . Immunoneutralization of
L-selectin reduced the number of tethering interactions, whereas
removal of the integrin did not impact upon tethering, but prevented
rolling, resulting in a very distinct pattern of leukocyte-endothelial
cell interactions of an initial capture and then detachment 29 . By
contrast, this pattern of glancing stop and go interactions was not
visualized in the present study following the addition of the
P-selectin or L-selectin Ab. This tends to support functional synergies
between L- and P-selectin for tethering and rolling rather than a
distinct tethering role for L-selectin or P-selectin. Nevertheless, the
inability of cells to roll via L-selectin in the absence of P-selectin
cannot be generalized to all vascular beds, since L-selectin can
support rolling of cell lines lacking ligands for P- or E-selectin in
the rat mesenteric microvasculature 30 . Moreover,
L-selectin-dependent rolling has been reported in P-selectin-deficient
mice 50 min post-trauma in the cremasteric microvasculature 20 ,
highlighting differences not just between tissues but also between
stimuli within the same tissue.
The current functional data fully support the existence of a vascular
endothelial ligand for L-selectin. Vascular L-selectin ligands on
activated microvascular and aortic endothelium have been reported
previously 31, 32, 33 . However, the leukocyte-associated P-selectin
ligand (PSGL-1)3 is also a
ligand for L-selectin 34, 35 , and some investigators have proposed
that PSGL-1 interactions with L-selectin may be important in rolling
leukocytes capturing additional leukocytes from blood and amplifying
leukocyte rolling 36, 37 . This mechanism cannot be excluded in our
model, as it is very difficult to discern leukocyte-leukocyte
interactions from leukocyte-endothelial cell interactions due to the
large numbers of rolling cells during responses to Ag in wild-type
mice. Nonetheless, a recent study of TNF--induced leukocyte
recruitment in the cremasteric microvasculature, which probably has
fewer rolling cells and is more amenable to examining
leukocyte-leukocyte interactions, estimated that capture of leukocytes
from the mainstream of blood by rolling or adherent leukocytes
accounted for only 1.2% of leukocyte recruitment in vivo 38 .
Moreover, the lack of effect of anti-L-selectin Ab treatment in the
absence of Ag, but a significant role in the presence of Ag, is more
consistent with the induction of a vascular L-selectin ligand rather
than leukocyte-leukocyte interactions. Otherwise, since PSGL-1 and
L-selectin are both constitutively expressed, leukocyte-leukocyte
interaction should occur under all circumstances (baseline and
Ag-challenged), and anti-L-selectin mAb should always be
inhibitory.
Despite a 60–70% reduction in the flux of rolling leukocytes (Fig. 2), L-selectin-deficient mice were capable of responding to Ag
challenge inasmuch as the number of leukocytes emigrating out of the
vasculature was similar to values observed in their wild-type
counterparts (Fig. 6). This observation is entirely consistent with a
requirement for >90% inhibition in leukocyte rolling before leukocyte
adhesion and emigration are subsequently inhibited in postischemic
vessels 39 . This further suggests that the transition from leukocyte
rolling to adhesion is not necessarily a linear relationship in every
vascular bed. Additionally, leukocytes rolled very slowly (10 µm/s)
in L-selectin-deficient mice (Figs. 1 and 2), which increases the
propensity of the rolling cells to adhere and emigrate when
appropriately stimulated 5, 40 . The slow rolling in
L-selectin-deficient mice is also a novel observation. To date, it has
been shown that E-selectin is responsible for slow rolling (10 µm/s
or less) in TNF--stimulated cremaster microvessels 41 . However,
the current data demonstrate for the first time an inflammation model
where sufficient P-selectin, but not E-selectin, mediates this type of
slow rolling. Similarly, ICAM-1 has recently been found to facilitate
selectin-mediated leukocyte rolling and to promote slower rolling
velocities for both P-selectin and L-selectin 5, 42 . Therefore, Ag
challenge may up-regulate both P-selectin and ICAM-1 expression
sufficiently to mediate very slow rolling in the absence of detectable
E-selectin function. The very slow rolling of leukocytes under these
conditions may also explain some of the increase in adhesion and
emigration observed in L-selectin-deficient mice following Ag challenge
(Fig. 6).
It is noteworthy that the lack of reduction in leukocyte accumulation in response to Ag in postcapillary venules of the cremaster muscle in L-selectin-deficient mice is different from findings reported in other tissues including the peritoneum and skin, wherein leukocyte recruitment was severely reduced in response to i.p. thioglycolate challenge, cutaneous delayed-type hypersensitivity responses, and cutaneous allograft sites 14, 15, 19 . By contrast, L-selectin-deficient mice also manifested a reduction in intracapillary accumulation of leukocytes during Escherichia coli-induced pneumonia but not in the ultimate emigration or edema formation 43 , a finding not different from our own studies. Clearly, L-selectin may play an important role in leukocyte recruitment into skin and peritoneum but a lesser role in leukocyte recruitment into lung 43 and into Ag-stimulated striated muscle microvasculature as proposed in this study. Moreover, the very significant overlapping role of P-selectin during leukocyte rolling in cremaster muscle is a likely explanation for the lack of reduced leukocyte recruitment in the L-selectin-deficient mouse.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paul Kubes, Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
3 Abbreviation used in this paper: PSGL-1, P-selectin ligand.
Received for publication July 2, 1998. Accepted for publication November 25, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4-integrin in acute, subacute, and chronic leukocyte recruitment in vivo. J. Immunol. 159:4514.[Abstract]
4-integrin, P-selectin, and E-selectin in an allergic model of inflammation. J. Exp. Med. 185:1.4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo. J. Exp. Med. 181:1995.
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 S. D. Robinson, P. S. Frenette, H. Rayburn, M. Cummiskey, M. Ullman-Cullere, D. D. Wagner, and R. O. Hynes Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment PNAS, September 28, 1999; 96(20): 11452 - 11457. [Abstract] [Full Text] [PDF]
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D. A. Steeber, M. L. K. Tang, N. E. Green, X.-Q. Zhang, J. E. Sloane, and T. F. Tedder Leukocyte Entry into Sites of Inflammation Requires Overlapping Interactions Between the L-Selectin and ICAM-1 Pathways J. Immunol., August 15, 1999; 163(4): 2176 - 2186. [Abstract] [Full Text] [PDF]
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