© 1997 American Heart Association, Inc.
Articles |
Emigrated Rat Neutrophils Adhere to Cardiac Myocytes via 
4 Integrin
From the Immunology (P.H.R., P.K.) and Cardiovascular (C.A.W., W.R.G.) Research Groups, University of Calgary (Canada).
Correspondence to Dr Paul Kubes, Immunology Research Group, Department of Medical Physiology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
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Abstract |
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Abstract Previous work has shown that neutrophils isolated from whole blood adhere to cardiac myocytes via CD18 (ß2 integrin) to cause injury to the heart cells. In vitro, we have found that upon endothelial transmigration, neutrophils can also express
4ß1; however, whether this
contributes to neutrophil adhesion to parenchymal cells remains
entirely unknown. Unstimulated and tumor necrosis
factor-–stimulated rat cardiac myocytes adherent to gelatin-coated
coverslips supported N-formyl-Met-Leu-Phe (fMLP)–induced
neutrophil (isolated from whole blood) adhesion entirely via CD18
(blocked with monoclonal antibody [mAb] WT-3). Emigrated neutrophils
spontaneously adhered to cardiac myocytes also entirely via CD18.
However, if fMLP was used to restimulate emigrated neutrophils, the
adhesion to cardiac myocytes was entirely independent of CD18. Although
an anti–4 integrin antibody (mAb TA-2) alone did not
reduce the emigrated neutrophil-myocyte interaction, dual
administration of TA-2 and WT-3 reduced adhesion by 81%.
4 integrin was expressed in small amounts on the surface
of circulating neutrophils, increased following transmigration, and
then increased >5-fold after restimulation of these emigrated
neutrophils. In the presence of the anti-CD18 antibody, a fibronectin
fragment (FN-40) but not a vascular cell adhesion molecule-1 antibody
(mAb 5F10) inhibited neutrophil-myocyte interactions by 80%. Similar
results were seen when the rat chemokine CINC-gro was used instead of
fMLP, suggesting that the 4-dependent adhesion was not
specific to fMLP. These data demonstrate that 4 integrin
can be physiologically induced to increase in
number and avidity after neutrophil emigration and that this adhesion
molecule can cause firm adhesion to fibronectin on parenchymal cells,
including rat cardiac myocytes.
Key Words: cardiac myocyte • neutrophil • adhesion • inflammation • 4 integrin
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Introduction |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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Myocardial inflammation associated with ischemia/reperfusion, sepsis, and other pathologies has been shown to have a major neutrophil component, inasmuch as prevention of neutrophil infiltration into myocardium decreases myocardial damage during the inflammatory process.1 2 3 4 Neutrophils are recruited to damaged myocardium by interacting with activated cardiac vascular endothelium in a sequential cascade of events. Selectin adhesion molecules that are expressed on both cell types initiate neutrophil tethering and rolling, whereas CD11/CD18 (a ß2 integrin) on neutrophils mediates firm adhesion by interacting with various ligands on endothelium (ICAM-1, etc).5 6 7 Adherent neutrophils then migrate through the endothelium toward the affected cardiac tissue by following increasing concentrations of chemotactic stimuli, such as fMLP from bacteria or chemokines such as CINC-gro or interleukin-8 from interstitial cells.
The mechanisms involved in neutrophil-myocyte interactions have not
been fully elucidated. As with adhesion to endothelium,
neutrophil adhesion to cardiac myocytes has been shown to be a
CD18/ICAM-1–mediated event.8 9 Moreover, the adhesion of
the neutrophils to cardiac myocytes was closely associated with myocyte
death.10 Although these studies were seminal in
demonstrating the importance of neutrophils and adhesion molecules in
cardiomyopathy, they differ critically from the
physiological condition in that the neutrophils
were isolated from whole blood (ie, circulating neutrophils). This
latter point is not trivial, inasmuch as neutrophils that have
emigrated in response to increasing concentrations of a chemotactic
gradient have been shown to express a novel adhesion molecule, the
4 integrin.11 4 integrin was
previously thought to be expressed on all leukocytes, with the
exception of neutrophils, and has been implicated in several disease
processes, including contact hypersensitivity,12 allergic
asthma,13 inflammatory bowel disease,14 and
cardiac allograft failure.15 Whether the observation that
emigrated neutrophils express 4 integrin can be extended
to suggest that these neutrophils will bind to myocytes via
4 integrins is highly speculative. Ligands for
4 integrin include the matrix protein fibronectin and
the adhesion molecule VCAM-1. Although VCAM-1 has not been detected on
quiescent or activated myocytes, fibronectin is expressed on
the surface of cardiac myocytes and may serve to support this adhesive
interaction.16 17
The objectives of the present study were to determine whether
emigrated neutrophils are able to adhere to cardiac myocytes and, if
so, to examine whether the adhesive profile that underlies the
neutrophil-myocyte interactions changes as a result of emigration. We
have used a static adhesion assay that allowed us to visualize
emigrated rat neutrophil adhesion to isolated rat cardiac myocytes and
report herein that whereas circulating neutrophils bind to
activated myocytes exclusively via the ß2
integrin, emigrated neutrophils increase expression and avidity of the
4 integrin, particularly after a second stimulus, and
firmly bind via this new adhesion molecule.
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Methods and Materials |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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mAbs and Reagents
mAb TA-2 (anti-rat
4) and WT-3 (anti-rat CD18)
were gifts from Dr Thomas Issekutz (University of Toronto,
Canada). Anti-rat VCAM-1 antibody (5F10) was a gift from Dr Roy Lobb
(Biogen, Inc, Cambridge Center, Mass). TNF- was a gift from Knoll
Pharmaceutical (Markum, Ontario, Canada). Purified human fibronectin
fragment 40K was purchased from Chemical International Inc. CINC-gro
was a gift from Dr Makato Suematsu, Keio University, Tokyo, Japan.
Unless otherwise stated, all other reagents were purchased from Sigma
Chemical Co. All cells used were obtained from Sprague-Dawley rats (225
to 275 g, Harlan Sprague Dawley, Inc, Indianapolis, Ind).
Neutrophil Isolation and Treatment
Circulating rat neutrophils were isolated from
citrate-anticoagulated whole blood collected by cardiac puncture.
Briefly, red blood cells were removed by dextran sedimentation followed
by hypotonic lysis. Neutrophils were further purified by
centrifugation through a Histopaque gradient and
resuspended in HBSS at 2x107/mL. To obtain emigrated
neutrophils, rats were injected intraperitoneally
with 10 mL of 1% oyster glycogen in PBS. After 4 hours, the rats were
killed, and the peritoneal fluid was collected. After
centrifugation, the emigrated neutrophils were
resuspended in HBSS at 2x107/mL. Neutrophils were
activated by treating them with 20 µmol/L fMLP or
10 nmol/L CINC-gro just before injection into the adherence
assay chambers (see below). Antibodies were added at the time of
activation.
Flow Cytometry
Circulating or emigrated rat neutrophils (1x106 per
tube) were fixed in 1% formalin (30 minutes at 4°C) and then washed.
TA-2 antibody (2 µg per tube) was added to stain for 4
integrin. After 30 minutes, the cells were washed and labeled with
FITC-conjugated goat anti-mouse IgG (Serotec) and incubated at room
temperature for a further 30 minutes. After washing, the level of
4 integrin expression was measured on a FACScan flow
cytometer (Becton Dickinson Immunocytochemistry Systems).
Cardiac Myocyte Isolation and Treatment
Right ventricular myocytes from rats were isolated
as previously described.18 Briefly, the heart was rapidly
removed from decapitated animals, and Tyrode's solution was perfused
retrogradely (10 mL/min for 5 minutes) via a canula attached to the
aorta. The heart was then perfused with Tyrode's solution containing
collagenase (0.02 mg/mL), protease (0.004
mg/mL), and taurine (2.4 mg/mL) for 7 minutes, after
which the right ventricle was separated from the heart and minced with
10 mL of Tyrode's solution containing collagenase (0.05
mg/mL), protease (0.1 mg/mL), taurine (2.5 mg/mL),
BSA (5 mg/mL), and CaCl2 (50 mmol/L).
After agitation for 10 to 20 minutes at 34°C, the supernatant
(containing separated myocytes) was collected and placed in Tyrode's
solution with BSA (5 mg/mL), taurine (2.5 mg/mL), and
CaCl2 (50 mmol/L). Taurine was added to prolong
the viability of the myocytes during storage.
To mimic an inflammatory state, tubes containing
ventricular myocyte suspensions (
1x104
cells/mL) were dosed with TNF- (300 U/mL) and placed on a rotating
rack for 4 hours at 37°C, after which the myocytes were layered onto
coverslips and incubated for 1 more hour (see below). Control myocytes
were subjected to the same protocol without dosing with TNF-.
Adhesion Assay
Round glass coverslips (25 mm, Bellco Glass Inc) were
pretreated with 1 mL of 1% gelatin in PBS for 60 minutes at 37°C.
The coverslips were washed once in PBS, and 1 mL of myocyte suspension
was gently layered onto the coverslip. The myocytes were allowed to
settle and adhere to the coverslips for 60 minutes at 37°C, after
which the coverslips were inserted into adherence assay chambers. The
chamber is designed to hold two coverslips separated by an O-ring
gasket (Bellco Glass Inc). Neutrophil suspensions (diluted to
1x106/mL in HBSS) were injected into the chamber and
allowed to settle onto the cardiac myocytes for 10 minutes, after which
the chambers were inverted. At this point, nonadherent neutrophils
settled to the other side of the chamber. This design allowed for
visualization of the cardiac myocytes (magnification, x200) using
phase-contrast microscopy with an inverted microscope (Zeiss Canada).
The number of adherent neutrophils per myocyte was determined for a
minimum of 16 myocytes on each coverslip, with each condition repeated
three to eight times.
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Results |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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Circulating Neutrophils Adhere to Cardiac Myocytes via CD18
Freshly isolated neutrophils from rat blood showed minimal adherence to unstimulated rat cardiac myocytes (Fig 1
). When neutrophils were stimulated with
fMLP, adhesion to myocytes increased significantly, an event that was
totally inhibitable by the addition of an anti-CD18 antibody (mAb
WT-3). Stimulation of cardiac myocytes with TNF- increased the level
of fMLP-stimulated neutrophil adhesion (Fig 1), and this interaction
was also inhibited by an anti-CD18 antibody. Fig 2 is a photomicrograph of the system used
in the present study illustrating fMLP-treated neutrophils adhering
to TNF-–stimulated myocytes.
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Emigrated Neutrophils Can Adhere to Cardiac Myocytes via a
CD18-Independent Mechanism
Emigrated neutrophils adhered to both unstimulated and
TNF-–stimulated cardiac myocytes (Fig 3). Once again, addition of the anti-CD18
antibody inhibited these interactions. When emigrated neutrophils were
exposed to a dose of chemoattractant (fMLP), the adhesion to cardiac
myocytes was further increased. However, the anti-CD18 antibody was
unable to inhibit the adhesion of emigrated neutrophils treated with
fMLP to either unstimulated or TNF-–stimulated cardiac
myocytes.
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Emigrated Neutrophils Express and Functionally Adhere via
4 Integrin
Fig 4 is a flow cytometric histogram
demonstrating 4 integrin expression (staining with mAb
TA-2) on circulating (from whole blood) and emigrated (elicited into
the peritoneal cavity) rat neutrophils. These data confirm the
observations of Issekutz et al,19 who reported a low level
of expression on circulating rat neutrophils. However, our data extend
previous work, inasmuch as emigration of neutrophils resulted in a
2-fold increase in 4 integrin expression (mean
fluorescence: circulating neutrophils, 7.0; emigrated
neutrophils, 14.0). Moreover, when emigrated cells were stimulated with
fMLP, a further increase in 4 integrin expression was
noted (mean fluorescence, 37.9). In fact, the difference for
4 integrin expression between circulating and
restimulated emigrated neutrophils was >5-fold. To determine if the
CD18-independent adhesion was attributable to 4
integrin, anti–4 integrin antibody (mAb TA-2) was added
to emigrated neutrophils that had been stimulated with fMLP. Whereas
neither antibody had an effect, tandem addition of TA-2 and WT-3
significantly decreased adhesion (Fig 5).
Similar results were seen for unstimulated cardiac myocytes (not
shown).
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Neutrophil 4 Integrin Binds to Fibronectin on
Cardiac Myocytes to Support Adhesion
The CD18-independent adhesion of emigrated neutrophils to
TNF-–stimulated myocytes could be inhibited if, in addition to an
anti-CD18 antibody, a fibronectin fragment (FN-40) was also added (Fig 6). This effect was dose dependent, as a
higher concentration of FN-40 (10 µg/mL) was more effective at
inhibiting adhesion. Much like the anti–4 integrin data
in Fig 5
, addition of FN-40 alone did not inhibit neutrophil adhesion.
Whereas inhibiting 4 integrin binding to fibronectin
abrogated adhesion, the addition of a polyclonal anti-rat VCAM-1
antibody (5F10) had no effect (Fig 6).
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CINC-gro Is Able to Stimulate 4 Integrin–Dependent
Adhesion of Emigrated Neutrophils to Cardiac Myocytes
To determine if other physiological agonists
are able to induce CD18-independent adhesion of emigrated neutrophils,
we tested the endogenous rat chemokine CINC-gro (10
nmol/L), a potent chemoattractant of rat neutrophils. As with
fMLP stimulation, the adhesion of CINC-gro–stimulated emigrated
neutrophils resulted in significant adhesion to TNF-–stimulated
cardiac myocytes, an event that was not inhibitable by anti-CD18 or
anti–4 integrin antibodies alone (Fig 7). When anti-CD18 antibody was used in
combination with the anti–4 integrin antibody or
the fibronectin fragment (10 µg/mL), significant
attenuation of adhesion was observed.
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Discussion |
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TopAbstractIntroductionMethods and MaterialsResultsDiscussionReferences |
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In vitro, we have previously shown that emigration across endothelium induces the expression of the ß1 integrin
4ß1 on human
neutrophils.11 The purpose of the present study was to
determine whether neutrophils use 4 integrin to adhere
to freshly isolated ventricular myocytes and whether this
event could be influenced by the inflammatory state of the myocyte. The
present study is the first to demonstrate that the
physiological event of emigration alters the
mechanisms by which neutrophils adhere to parenchymal cells such as
cardiac myocytes. Both circulating (ie, isolated from whole blood) and
emigrated rat neutrophils adhered to rat cardiac myocytes via CD18.
This occurred regardless of the inflammatory state of the myocyte.
Application of the chemoattractant fMLP or CINC-gro to emigrated
neutrophils resulted in increased adhesion. However, the anti-CD18
antibody was unable to inhibit the adhesion of emigrated neutrophils
treated with chemoattractant to either unstimulated or
TNF-–stimulated myocytes, whereas coadministration of antibodies
against CD18 and 4 integrin did inhibit >80% of the
adhesion. Thus, emigration induced a second adhesive mechanism on
neutrophils, mediated by 4 integrin.
These data suggest that the ligand for CD18 is constitutively expressed
on rat cardiac myocytes and is increased with inflammatory
cytokine stimulation. Previous studies have established the
importance of CD18 in neutrophil adhesion to cardiac myocytes under
conditions in which both the neutrophil and the myocyte were
stimulated.8 We have found significant adhesion when only
the neutrophils were stimulated. This may be due to differences in the
models used (rat versus canine). Whereas canine cardiac myocytes do not
express ICAM-1 unless they have been stimulated with an inflammatory
cytokine,9 cultured neonatal rat myocytes are
known to constitutively express ICAM-1, the level of which can be
increased with TNF- stimulation.20 Our data suggest
that this may also be the case for adult rat myocytes, although the
expression of other potential CD18 ligands (eg, ICAM-2) cannot be
excluded.
The induction of 4 integrin may strengthen the adhesive
interaction between neutrophils and extravascular tissue, thus
anchoring the emigrated neutrophil firmly to an inflammatory site.
Alternatively, 4 integrin may be important for
extravascular adhesion when ligands for CD18 are reduced or not
present. Interestingly, circulating neutrophils or emigrated
neutrophils that were not restimulated with chemoattractant did not
demonstrate 4 integrin–dependent adhesion, despite the
presence of 4 integrin in both situations. The reasons
for this may be 2-fold. First, the level of 4 integrin
expression may have been insufficient to support adhesion. This
observation is consistent with our flow cytometric experiments,
inasmuch as restimulation of emigrated neutrophils with fMLP increased
4 integrin expression 5-fold. Dalton et
al21 have demonstrated that ß1 integrin
surface expression is lost if the integrin does not engage its ligand.
It is conceivable that elicited neutrophils isolated from the
peritoneal cavity are nonadherent and might be expected to therefore
have reduced expression of surface integrins. Chemoattractant
stimulation may function to remobilize the 4 integrin
that was expressed during emigration. An alternative explanation for
the need for restimulation may be that the binding affinity of the
4 integrin may be reduced. Indeed, it is well known that
4 integrin can be in a low- or high-affinity state and
that perhaps glycogen-elicited neutrophils require further stimulation
to activate 4 integrin. This closely mimics the
pathophysiological condition; such an increase in
stimulation with chemotactic agents would occur as neutrophils
emigrated toward an inflamed site. Although this has not been
previously described for 4 integrin, Hughes et
al22 have demonstrated that newly mobilized Mac-1
(CD11b/CD18) is capable of functioning in adhesion only if the
neutrophils are subsequently exposed to an increased level of
stimulus.
In the present study, emigrated neutrophils had to be restimulated
with an exogenous signal. Even TNF-–stimulated myocytes were unable
to deliver an activating signal to emigrated neutrophils to induce the
4 integrin–dependent adhesion. However, this may be due
to the low density of myocytes in our model versus the case in vivo,
where emigrated neutrophils are closely associated with a large number
of inflamed cardiac myocytes and in the presence of many
interstitial cells (including mast cells and fibroblasts).
These cells are known to produce many proinflammatory molecules in
myocardial inflammation; the complement fragment C5a has been found in
cardiac lymph during reperfusion of the ischemic
heart23 and in bacterial products such as fMLP in
bacteria-associated myocarditis. Moreover, mast cells release many
different stimuli, including platelet activating factor,
leukotrienes, and TNF-, all capable of activating
neutrophils. Thus, in vivo, it is likely that emigrated neutrophils
would be exposed to higher concentrations of endogenously
derived agonists than are present in our experimental model, a
situation that may invoke 4 integrin–mediated
adhesion.
4 integrin can support leukocyte adhesion by binding to
VCAM-1 or to fibronectin. Anti–VCAM-1 antibody (5F10) had no effect on
CD18-independent adhesion, suggesting that VCAM-1 is not important for
adherence in this model. Fibronectin is a constituent of the cardiac
extracellular matrix and is found within the transverse tubules of
cardiac myocytes.17 During inflammatory episodes,
immunoreactivity for fibronectin increases in affected cardiac tissue
and is associated with penetration of fibronectin into the
myocytes.16 The 4 integrin–dependent
adhesion of neutrophils to myocytes was inhibited by the addition of
FN-40 (Fig 6). As with the anti–4 integrin antibody,
the inhibitory effect was revealed only in the presence of
anti-CD18 antibody. Because fibronectin is constitutively present
on heart tissue, the lack of requirement for protein synthesis may be
significant during postischemic neutrophil influx into
affected heart tissue, where emigrated neutrophils would find a readily
available ligand for newly expressed 4 integrin.
Whether this newly identified adhesive pathway is
physiologically relevant remains to be
resolved. To date, anti-CD18 antibodies have confirmed that the
ß2 integrin adhesion pathway is important in, for
example, myocardial ischemia/reperfusion. However, this is
almost certainly due to the fact that neutrophils were prevented from
adhering to the endothelium via CD-18 and therefore
were unable to interact with the postischemic myocyte. In
fact, it may not be technically feasible to resolve the importance of
CD18 and 4 integrin as adhesive mechanisms involved in
parenchymal cell adhesion in vivo. It is interesting that in some
studies the protective effect of 4 integrin antibodies
could be dissociated from leukocyte recruitment13 24 and
begs the question of whether inhibition of adhesion to parenchymal
cells can account for some of this protection. Related to this issue,
Entman et al10 have demonstrated that preventing
neutrophil adhesion to myocytes with antiadhesive therapy does reduce
canine myocyte death. In the present study, we saw few myocytes
die, even when numerous activated neutrophils were observed to
adhere to myocytes. This may be related to differences between dog and
rat myocytes or incubation conditions (eg, we use taurine, an
antioxidant, in our isolation procedure). The lack of myocyte death
following neutrophil adhesion does not preclude the possibility that
more subtle dysfunction has occurred in these cells and certainly
warrants further investigation.
It is apparent that the myocardial damage is due to neutrophil
interaction with myocytes under various inflammatory conditions. The
present study demonstrates that after emigration, CD18 continues to
be important in mediating neutrophil adhesion to cardiac myocytes.
However, emigration of neutrophils invokes a second adhesive mechanism,
namely, 4 integrin. This emigration-dependent adhesive
mechanism may require some consideration in designing drugs to inhibit
neutrophil/myocyte interactions.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors gratefully acknowledge support from the Canadian Medical Research Council.
Received January 27, 1997; accepted May 29, 1997.
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References |
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S. Raiden, Y. Pereyra, V. Nahmod, C. Alvarez, L. Castello, M. Giordano, and J. Geffner Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits neutrophil recruitment in the lung triggered by fMLP J. Leukoc. Biol., November 1, 2000; 68(5): 700 - 706. [Abstract] [Full Text]
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J. Werr, E. E. Eriksson, P. Hedqvist, and L. Lindbom Engagement of {beta}2 integrins induces surface expression of {beta}1 integrin receptors in human neutrophils J. Leukoc. Biol., October 1, 2000; 68(4): 553 - 560. [Abstract] [Full Text]
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 J. Werr, J. Johansson, E. E. Eriksson, P. Hedqvist, E. Ruoslahti, and L. Lindbom Integrin alpha 2beta 1 (VLA-2) is a principal receptor used by neutrophils for locomotion in extravascular tissue Blood, March 1, 2000; 95(5): 1804 - 1809. [Abstract] [Full Text] [PDF]
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M. G. Simms and K. R. Walley Activated macrophages decrease rat cardiac myocyte contractility: importance of ICAM-1-dependent adhesion Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H253 - H260. [Abstract] [Full Text] [PDF]
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B. Y. Poon, C. A. Ward, W. R. Giles, and P. Kubes Emigrated Neutrophils Regulate Ventricular Contractility via {alpha}4 Integrin Circ. Res., June 11, 1999; 84(11): 1245 - 1251. [Abstract] [Full Text] [PDF]
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 J. Werr, X. Xie, P. Hedqvist, E. Ruoslahti, and L. Lindbom beta 1 Integrins Are Critically Involved in Neutrophil Locomotion in Extravascular Tissue In Vivo J. Exp. Med., June 15, 1998; 187(12): 2091 - 2096. [Abstract] [Full Text] [PDF]
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K. L. Davenpeck, S. A. Sterbinsky, and B. S. Bochner Rat Neutrophils Express alpha 4 and beta 1 Integrins and Bind to Vascular Cell Adhesion Molecule-1 (VCAM-1) and Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) Blood, April 1, 1998; 91(7): 2341 - 2346. [Abstract] [Full Text] [PDF]
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