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Adhesion Molecules: The Path to a New
Understanding of Acute Inflammation
Barbara Walzog and Peter Gaehtgens
A
t the end of the last century, Elie Metchnikoff laid the foundation for the biological theory of inflammation by
realizing that the acute inflammatory response “consists in a
reaction of phagocytes against a harmful agent” (8). In the following 100 years, this theory was consolidated and extended
by recognizing the molecular mechanisms that underlie the
activation and recruitment of the leukocytes from the circulation and their trafficking through the body. The identification of
the nature of adhesion molecules and inflammatory mediators
involved not only expanded our knowledge of the molecular
mechanisms but also provided the basis for a new understanding of the inflammatory response and its role in tissue homeostasis. This review focuses on the importance of adhesion
molecules in the control of acute inflammation, which is characterized by immediate infiltration of polymorphonuclear neutrophils (PMN) at sites of lesion, followed by monocytes and
eventually lymphocytes.
Human host defense includes physical and chemical barriers, e.g., skin and mucous membranes as well as gastric
acidity or secretory and excretory flow, and so forth. Agents
that overcome these barriers are faced with the innate
and/or acquired defense mechanisms designed to recognize
and eliminate foreign materials. These mechanisms, which
are based on the sophisticated functions of the leukocytes,
are also responsible for the elimination of old, damaged, or
“unwanted” cells and thereby contribute to the maintenance of tissue homeostasis. Thus host defense mechanisms
not only protect the organism from infection but also allow
the removal of cell debris and destroyed tissue components
that may result, for example, from ischemia or trauma. As a
part of the innate defense, the acute inflammatory response
that is elicited on these biological, chemical, or physical
noxae allows leukocyte recruitment, i.e., the rapid and sitedirected traveling of leukocytes to their target regions within
B. Walzog and P. Gaehtgens are in the Department of Physiology, Freie
Universität Berlin, Arnimallee 22, D-14195 Berlin, Germany.
0886-1714/99 5.00 © 2000 Int. Union Physiol. Sci./Am.Physiol. Soc.
the body, the first of four prerequisites for an effective host
defense at sites of lesion. In a second step, leukocytes
develop specific instruments that are responsible for the
elimination of foreign materials or damaged tissue cells.
This destructive potential of the leukocytes is prevented
from causing uncontrolled tissue damage by containment
mechanisms allowing graduation and finally resolution of
the acute inflammatory response. Finally, inflammation
gives rise to the process of repair and wound healing, which
permits restitutio ad integrum.
How are leukocytes made to leave the circulation? The
multistep paradigm of leukocyte recruitment
Metchnikoff (8) was convinced that leukocyte recruitment
represents an active process that is managed by the leukocytes alone, whereas Cohnheim (4) and other investigators
had the idea that leukocyte emigration depends on the properties of the vessel wall. The identification of the molecules
involved in this recruitment process showed that emigration
depends on sophisticated interaction between leukocytes
and endothelial cells, to which both cell types actively contribute by expressing adhesion molecules on their surfaces
and secreting soluble mediators. The sequence of events that
allows the traveling of leukocytes to sites of host defense is
designated the multistep paradigm of leukocyte recruitment
(10). It involves margination and capturing of free-flowing
leukocytes, leukocyte rolling, activation, firm adhesion, and
spreading, transendothelial diapedesis, and chemotactic
migration of the leukocytes (Fig. 1). The prerequisite for all of
these steps is the activation of the endothelial cell monolayer
by tissue-derived signals that induce the expression of
endothelial adhesion molecules and trigger the secretion of
inflammatory mediators by endothelial cells.
Since leukocytes represent the largest particles in the circulating blood, they normally tend to travel in the axial
blood stream of the microvessels. Hydrodynamic margination, i.e., radial displacement and retardation, is therefore
required to bring the white blood cells into a critical
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About 100 years after the definition of the basic principles of inflammation, the identification of the
underlying molecular mechanisms provides a new understanding of the inflammatory response.
The specificity and diversity of the adhesion molecules involved in leukocyte extravasation
account for the ordered leukocyte recruitment and activation in inflammation.
Table 1.
Adhesion molecules involved in leukocyte trafficking
Adhesion molecule
Selectins
L-Selectin
P-Selectin
E-Selectin
Immunoglobulins
ICAMs
ICAM-1
ICAM-2
ICAM-3
VCAM-1
PECAM-1
Major occurrence
Major ligands
CD62L
CD62P
CD62E
Leukocytes
Endothelial cells, platelets
Endothelial cells
CD34, Glycam-1, MAdCam-1, PSGL-1
PSGL-1
ESL-1, PSGL-1
CD49d/CD29, VLA-4
Lympocytes, monocytes
VCAM-1, fibronectin
CD11a/CD18, LFA-1
CD11b/CD18, Mac-1
CD11c/CD18, gp150/95
CD11d/CD18
Leukocytes
Neutrophils, monocytes
Neutrophils, monocytes
Lymphocytes
ICAM-1, -2, -3
ICAM-1, fibrinogen, C3bi, factor X
ICAM-1, fibrinogen, C3bi
VCAM-1, ICAM-3
CD51/CD61
Leukocytes
Vitronectin, CD31
CD49d/β7
CD103/β7
Lymphocytes
Lymphocytes
VCAM-1, MAdCam-1
E-cadherin
CD54
CD102
CD50
CD106
CD31
Endothelial cells
Endothelial cells
Leukocytes
Endothelial cells
Neutrophils, monocytes,
platelets, endothelial cells
LFA-1, gp150/95
LFA-1, (Mac-1)
LFA-1, αD/β2
α4/β1, α4/β7
CD31, av /β3
Leukocytes
Endothelial cells
Hyaluronan
?
Others
CD44
VAP-1
For further details, see Ref.1
proximity to the endothelial cell monolayer lining the
blood vessels. This allows the initial cell-to-cell contact
between leukocytes and endothelial cells mediated by adhesion molecules: the capturing of free-flowing leukocytes.
The subsequent leukocyte rolling along the vessel wall is
supported by transient contacts between adhesion molecules of activated endothelial cells and leukocytes. Due to
their reduced speed, leukocytes are now sufficiently exposed
to inflammatory mediators secreted by the endothelial cells,
and, if activated, firmly adhere via their adhesion molecules
and spread on the endothelial surface. This is the prerequisite for transendothelial migration, which is in general
thought to occur through the intercellular junctions of
neighboring endothelial cells. This process is not only due to
locomotion of the leukocytes but also requires an active
contribution of the transmigrated endothelial cells. Thereby,
the cells exhibit adhesion molecule-mediated cell-to-cell
contacts that guide the leukocytes in a way that is not yet
entirely understood. After passing the basement membrane,
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leukocytes migrate chemotactically toward their final destination—a process that was originally recognized by Rudolf
Virchow (11)—and are again directed by adhesion molecule
interaction with the elements of the tissue fiber matrix.
Although leukocyte recruitment generally follows these
basic principles, the underlying molecular mechanisms show
great versatility in detail. Depending on the inflammatory stimulus, the leukocyte population recruited, the tissue, and the
context of activation, different adhesion molecules and inflammatory mediators are involved. This allows the temporal and
spatial regulation of targeting distinct leukocyte populations to
distinct destinations within the body. During acute inflammation, PMN are mobilized within minutes to hours upon stimulation, whereas monocytes accumulate at sites of lesion with a
time lag of approximately one day. PMN (and monocytes) emigrate from postcapillary venules, and naive lymphocytes emigrate preferentially from venules in secondary lymphoid organs,
which, due to their characteristic endothelial lining, are called
high-endothelial venules (HEV). Lymphocytes reenter the
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Integrins
β1-integrins
α4/β1
β2-integrins
αL/β2
αM/β2
αX/β2
αD/β2
β3-integrins
αv /β3
β7-integrins
α4/β7
αE/β7
Synonyms
blood stream and recirculate with preference for a specific
tissue (homing). Memory lymphocytes are known to emigrate
primarily from post-capillary venules and enter “their” secondary lymphoid organ via the afferent lymph.
How do leukocytes penetrate tissue in a targeted fashion?
A pivotal role for adhesion molecules
In inflammation, soluble mediators initiate cellular activation of leukocytes and endothelial cells, whereas adhesion
molecules allow the interaction of free-flowing leukocytes
with the vessel wall and all subsequent adhesive interactions
that are required for emigration into the tissue. The diversity
and specificity of the engaged adhesion molecules account
for the ordered leukocyte recruitment, which allows that
leukocytes meet and finally eliminate foreign particles with
great efficiency within a reasonable time.
Various families of adhesion molecules are involved in
leukocyte-endothelial cell interactions. These include selectins,
integrins, immunoglobulins, and other molecules as listed in
Table 1. Expressed on the cell surface, adhesion molecules
recognize and bind specific ligands, e.g., other adhesion
molecules or extracellular matrix proteins, and thereby mediate cell-cell and cell-substrate interactions. All adhesion molecules show a characteristic cellular distribution. Variations
are due, for example, to the level of expression, posttranslational modification of the molecules, differential splicing,
constitutive and/or inducible expression following cellular
activation, and so forth.
Selectins. The selectin family consists of three different
molecules: L-selectin, P-selectin, and E-selectin, which play
an important role in leukocyte capturing and rolling on
endothelial cells (7). L-selectin is constitutively expressed on
almost all leukocytes (L) and only virtually absent on a subset of memory lymphocytes. Whereas L-selectin expression is
restricted to leukocytes, P-selectin is constitutively expressed
on platelets (P) and induced, for example, on thrombin- or
histamine-activated endothelial cells. E-selectin is expressed
on activated endothelial (E) cells on stimulation by, for example, tumor necrosis factor-α (TNF-α) or interleukin 1. All
selectins are monomeric molecules that span the plasma
membrane once and contain a short epidermal growth factorlike repeat and two (L), six (E), or nine (P) complement
control protein-like repeats (Fig. 2). The characteristic Ca2+dependent lektin domain at the NH2 terminus defines their
affinity to specific carbohydrate ligands.
L-selectin binds several ligands, including glycam-1,
CD34, and MAdCAM-1 on high endothelial venules, a yetunidentified inducible ligand on activated microvascular
endothelium in postcapillary venules, and an unidentified
constitutive ligand on PMN, which is probably different from
the P-selectin ligand PSGL-1, on leukocytes. All L-selectin
ligands identified so far share common features: they are sialylated, fucosylated, sulfated, and show similarity to sialyl
Lewis x and Lewis x. An important function of selectins is
defined by their ability to bind carbohydrate ligands within
milliseconds, thereby capturing free-flowing leukocytes from
the bloodstream. This allows subsequent leukocyte rolling,
which markedly decreases the traveling speed of the leukocytes from >2000 µm/s to <50 µm/s. This specialized function, which represents a hallmark of leukocyte recruitment,
requires rapid association and dissociation of the selectinligand interaction and is well defined, especially for L-selectin.
Contact initiation of free-flowing leukocytes is further supported by the exposed localization of L-selectin at the tips of
microvilli (13). On PMN activation by, for example, soluble
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FIGURE 1. The multistep paradigm of leukocyte recruitment. PMN, polymorphonuclear neutrophils; EC, endothelial cells.
mediators, L-selectin is proteolytically cleaved from the cell
surface by the action of a specific enzyme and the shed extracellular portion of the molecule, soluble or sL-selectin, is
present in the plasma. There is broad conformity in the literature that sL-selectin levels in the plasma are elevated in
infectious diseases and inflammation, which can be regarded
as a rather nonspecific phenomenon reflecting elevated
leukocyte counts in the circulation and/or enhanced leukocyte turnover. Although sL-selectin has been proposed to
act as a putative competitive inhibitor of membrane-bound
L-selectin, its functional relevance remains to be proven.
Other data support the concept that shedding of L-selectin
from the leukocyte surface controls the rolling velocity,
which in turn has an impact on the transit time of the leukocytes. Thus L-selectin shedding may reduce the exposure of
the leukocytes to endothelial-derived inflammatory mediators and thereby may restrict extravasation.
P-selectin and E-selectin also contribute to leukocyte rolling
on the activated endothelial surface. P-selectin is stored in the
Weibel-Palade bodies of endothelial cells and in the α-granules
of platelets. On activation of endothelial cells, P-selectin is
rapidly recruited to the cell surface, whereas E-selectin expression requires de novo synthesis induced by several inflammatory mediators. Both P- and E-selectin bind carbohydrate
ligands on leukocytes and thereby mediate leukocyte rolling
on activated endothelial cells. The major ligand of P-selectin
on leukocytes is PSGL-1, which also shows some affinity for
E-selectin. E-selectin recognizes ESL-1 on leukocytes. Similar
to L-selectin, the extracellular portions of P- and E-selectin,
sP-selectin, and sE-selectin, are present in the plasma.
Besides direct interactions with endothelial cells, leukocytes are also conducted to the endothelial monolayer by
platelets, forming a bridge while binding, for example, to
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peripheral node addressin (PNAd) via P-selectin. Leukocytes
that adhere to the vessel wall can also capture free-flowing
leukocytes from the circulation. Thus a broad variety of cellular and molecular mechanisms contribute to the initial contact between leukocytes and endothelial cells.
Integrins. Integrins mediate the firm adhesion of leukocytes
by binding members of the immunoglobulin family of adhesion molecules expressed on endothelial cells. Integrins are
heterodimeric molecules consisting of an α-subunit and a
noncovalently-bound β-subunit. They represent a large protein family that is classified by the β-subunits. β1- (CD29),
β2- (CD18), β3- (CD61), and β7-integrins are engaged in
leukocyte recruitment, with β2-integrins playing the key role
in mediating firm adhesion of human PMN subsequent to
selectin-mediated rolling. Leukocyte rolling constitutes a prerequisite for β2-integrin-mediated firm adhesion in vivo, since
β2-integrins are not able to bind their ligands unless the
velocity of passing leukocytes is slowed down to a critical
value by selectin-based rolling.
There exist four different β2-integrins (CD11/CD18) designated
according to the α-subunit: lymphocyte function-associated
antigen 1 or LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18),
gp150/95 (CD11c/CD18), and CD11d/CD18. β2-integrins
mediate firm adhesion of leukocytes to endothelial cells by
binding to intercellular adhesion molecules (ICAMs), members of the immunoglobulin superfamily that are expressed
by endothelial cells. The most important β2-integrin that mediates firm adhesion is LFA-1, which is constitutively expressed
on virtually all leukocytes. LFA-1 exerts its function primarily
by binding ICAM-1, which is upregulated on the inflamed
endothelium. Mac-1 also has some affinity for ICAM-1, but
its role in mediating adhesion is thought to be less important.
LFA-1 also binds to ICAM-2, which is constitutively expressed
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FIGURE 2. Structure of adhesion molecules involved in leukocyte recruitment. ICAM, intercellular adhesion molecule; VCAM, vascular adhesion molecule; PECAM, platelet endothelial cell adhesion molecule.
of leukocytes. E-cadherin also binds αE/β7 and may contribute to lymphocyte homing to intestinal epithelium.
Besides this, other molecules, such as CD44 and vascular
adhesion protein 1 (VAP-1), may be involved in leukocyte
trafficking, but the biological significance of these are still
under investigation.
How is the inflammatory cascade initiated? Insights from
the molecular mechanisms of leukocyte-endothelial cell
interactions
Adhesion and emigration. The acute inflammatory response
elicited upon invasion of microorganisms or upon tissue
damage is associated with the release of proinflammatory
mediators by tissue macrophages, mast cells, or other tissue
cells such as damaged fibroblasts. Soluble mediators like histamine, interleukin 1, and TNF-α activate the endothelium
lining postcapillary venules, i.e., they induce the expression
of adhesion molecules and the secretion of soluble mediators, which in turn allow the leukocyte-endothelial cell
interactions. The diversity and specificity of the adhesion
molecules expressed constitute the molecular basis for the
“The acute inflammatory response…is associated
with the release of proinflammatory mediators
by tissue macrophages, mast cells,
or other tissue cells….”
site-directed traveling of leukocytes during inflammation (2).
The sequence of molecular mechanisms during PMN recruitment in acute inflammation is shown in Fig. 3. The induction
of the L-selectin ligand on the microvascular endothelium by
tissue-derived proinflammatory mediators allows initial capture and rolling of PMN via L-selectin. Rolling is also supported by upregulation of endothelial P- and E-selectin,
which serve as receptors for PSGL-1 and ESL-1. PMN recruitment subsequent to rolling critically requires β2-integrinmediated firm adhesion of the PMN to the endothelial cells.
Patients suffering from leukocyte adhesion deficiency type I,
an inheritable defect of the CD18 gene of the β2-integrins,
show a lack of inflammatory response: PMN extravasation
does not occur despite the presence of inflammatory agents
(6). This is consistent with the finding that gene-targeted
CD18-deficient mice show impaired PMN recruitment. In
contrast, extravasation of monocytes that predominantly emigrate via β1-integrin-dependent mechanisms is not diminished in the absence of β2-integrins (15). The dependence of
PMN emigration on β2-integrins is thought to result from their
ability to bind ICAM-1 on activated endothelial cells. Adhesive interactions of the β2-integrins require integrin activation,
i.e., functional upregulation of their ligand-binding affinity by
a process termed inside-out signaling. It is elicited by soluble
inflammatory mediators from activated endothelial cells to
which the PMN are exposed while rolling on the inflamed
vessel wall. Thus substantial PMN recruitment from the circulating blood can only occur if endothelial cells are sufficiently activated to stimulate the PMN to activate β2-integrins
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by endothelial cells. Moreover, LFA-1 recognizes ICAM-3,
which is expressed on leukocytes and mediates leukocyteleukocyte interaction. Besides the affinity for ICAM-1, Mac1 shows affinity for ligands such as fibrinogen, factor X, and
C3bi. gp150/95 binds ICAM-1, fibrinogen, and C3bi.
CD11d/CD18 is a receptor for VCAM-1 and ICAM-3. β2-integrins as well as other integrins are physically linked to the
integrin-associated protein IAP (CD47), which is thought to
contribute to the regulation of integrin function.
The β1-integrins are primarily expressed on lymphocytes and
monocytes. Very late antigen 4 (VLA-4, α4/β1, CD49d/CD29)
plays a major role in mediating monocyte extravasation by
binding to inducible vascular adhesion molecule 1 (VCAM-1,
CD106). β1-integrins have a subordinate function in extravasation of PMN, which show only minimal expression of this integrin. The αv/β3-integrin (CD51/CD61) serves as a receptor for the
extracellular matrix protein vitronectin and plays a role in
migration of PMN. The α4/β7-integrin (CD49d/β7) binds MAdCAM-1 and VCAM-1 and mediates lymphocyte homing to
Peyer’s patches and the lamina propria.
Immunoglobulins. The most important adhesion molecules
of the immunoglobulin superfamily that serve as ligands for
the integrins during leukocyte-endothelial cell interactions are
the ICAMs termed ICAM-1 (CD54), ICAM-2 (CD102), ICAM3 (CD50), and VCAM-1 (CD106). ICAM-1 is strongly upregulated on endothelial cells upon activation by inflammatory
mediators such as TNF-α. ICAM-1 binds LFA-1 with strong
affinity, shows some affinity for Mac-1, and putatively binds
gp150/95. As mentioned above, ICAM-1 serves as the major
endothelial ligand that mediates firm adhesion of PMN to
inflamed endothelial cells and therefore plays a central role in
PMN recruitment to sites of inflammation. In contrast to
ICAM-1, ICAM-2 is constitutively expressed on endothelial
cells and its expression is virtually unaffected by inflammatory
mediators. ICAM-2, which binds LFA-1 with high affinity, is
also expressed on some leukocyte populations but is absent
on PMN. ICAM-2 is considered to be involved primarily in
lymphocyte homing. ICAM-3 (CD50) is highly expressed on
leukocytes but absent on endothelial cells. ICAM-3 binds
LFA-1 with high affinity and thereby mediates leukocyteleukocyte interactions. VCAM-1 (CD106) is expressed primarily on endothelial cells and is upregulated upon stimulation
by various inflammatory mediators, especially cytokines.
VCAM-1 plays a role in mediating leukocyte-endothelial
interactions by binding to the α4/β1 and the α4/β7-integrins as
well as to the β2-integrin CD11d/CD18. Platelet endothelial
cell adhesion molecule (PECAM-1) (CD31), another member
of the immunoglobulin family, is highly expressed on PMN
and monocytes as well as on endothelial cells, exerts homotypic interactions, and binds to αv/β3. CD31 is considered to
mediate leukocyte-endothelial cell interactions as well as
transendothelial migration of leukocytes.
Other adhesion molecules. Cadherins represent another
family of adhesion molecules that is primarily characterized
by exerting homotypic adhesion. E-cadherin is expressed on
endothelial cells at close cellular contacts in the adherens
junctions. Dissociation of the E-cadherin interactions is currently considered to occur during transendothelial migration
and firmly adhere to the vessel wall. Besides soluble mediators, engagement of L-selectin and PSGL-1 is also considered
to trigger the functional upregulation of β2-integrins and
thereby support firm adhesion. Adherent PMN spread on the
endothelium transmigrate through the intercellular junctions
of the endothelial cells and finally penetrate the basement
membrane. Recent data suggest that adhesion preferentially
occurs near the margins of the endothelial cells and thus in
the vicinity of the endothelial junctions, through which the
PMN eventually escape.
Chemotactic migration. The finding that adhesion molecules are responsible for the targeting of leukocytes to
inflamed areas led to reinvestigation of how different leukocyte populations become selectively activated to emigrate
and navigate through the tissue space. Subsequent to firm
adhesion and transendothelial migration, the leukocytes are
recruited chemotactically to their target regions by a variety
of soluble mediators (12) . Although the major principles of
chemotactic migration of leukocytes are well documented,
especially by in vitro experiments (5), the way chemoattractants direct their effector cells in inflammation is not entirely
understood. This is due to the great complexity of this process
in vivo, where many different mediators act in concert, are
released by different cell types upon various stimuli, show
pleiotropic functions, and act on different cell types.
Chemoattractants that guide PMN during inflammation
include classical inflammatory mediators such as plateletactivating factor (PAF), leukotriene B4 (LTB4), chemoattractant cytokines such as interleukin-8 (which are also designated as chemokines), the complement factor C5a, and exogenous components like bacteria-derived peptides such
as the N-formylated tripeptide Met-Leu-Phe. Chemoattractants exert their effects by binding to specific receptors on the
leukocyte surface that share common features: they are hep112
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tahelical molecules with seven transmembrane domains that
activate intracellular signal transduction cascades via GTPbinding proteins (G proteins). Some of these receptors,
including that for interleukin 8, show promiscuous ligand
binding by exerting affinity to other structurally related
chemoattractants, i.e., the chemokines epithelial-derived
neutrophil attractant-78 (ENA-78), neutrophil activating peptide 2 (NAP-2), and melanoma growth-stimulating activity
(GRO). Moreover, some chemoattractants bind to different
receptors, whereas one type of receptor is often expressed
by more than one leukocyte population: bacteria-derived
N-formyl-peptides, for example, are chemoattractants for
both PMN and monocytes. Other mediators, like secondary
lymphoid tissue chemokine (SCL), which attracts T cells, or
B lymphocyte chemoattractant (BCL), which is chemotactic
for B cells, act primarily on lymphocytes.
How is the activation of PMN controlled and prevented
from exploding? Development of weaponry and
mechanisms of containment
The pattern of adhesion molecules expressed represents
the critical checkpoint for leukocyte extravasation in inflammation by determining the quantity and quality of leukocyte-endothelium interactions as well as its time course. This
has unequivocally been shown by the use of monoclonal
antibodies or by gene disruption in experimental animals.
But adhesion molecules also play a important role subsequent to PMN emigration. Severe inflammatory responses
are eventually accompanied by plasma exudation, which
allows clotting in the extravascular space. This provides an
appropriate matrix for β2-integrin-mediated adhesion of emigrated PMN. By serving as receptor for C3bi-opsonized
material, the β2-integrin Mac-1 also facilitates phagocytosis
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FIGURE 3. Molecular events of PMN-endothelial cell interactions in inflammation. PSGL, P-selectin ligand; ESL, E-selectin ligand.
How is the process of repair and tissue remodeling
initiated? Toward a new definition of inflammation
Although the mechanisms of inflammation described above
are still within the framework of Metchnikoff’s concept, growing evidence implies that the inflammatory response must be
placed into a greater context of tissue homeostasis. Beyond its
immediate physiological function, the inflammatory reaction
seems to cover more than an effective host defense mechanism. Patients suffering from leukocyte adhesion deficiency
type I not only show compromised leukocyte recruitment due
to the absence of β2-integrins but also show impaired wound
healing. Thus inflammatory leukocyte infiltration seems to
give rise to wound repair and tissue remodeling, which eventually allows restitutio ad integrum. On the molecular and cellular levels, this requires production and reconstitution of
extracellular matrix, cell proliferation and differentiation, as
well as more complex processes such as induction of angiogenesis and vascularization. Growing evidence suggests that
these processes can be initiated or promoted by inflammatory cytokines such as interleukin-1, which induces, for
example, proliferation of fibroblasts and matrix production.
The present evidence that the inflammatory response does
not end with the elimination of foreign particles may imply
the requirement of a novel definition of inflammation. However, the biological significance of these findings remains to
be proven and further investigations are required to provide
the molecular basis for the understanding of the mechanisms
by which inflammation may integrate host defense, wound
repair, and tissue remodeling.
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and thereby promotes clearance of the tissue from foreign
particles. PMN destroy ingested material by reactive oxygen
metabolites, which are produced upon activation of NADPH
oxidase. The destructive potential of PMN is further due to
the contents of granules, i.e., enzymes such as elastase and
cathepsin G, myeloperoxidase, and others, which can be
released from the cells by exocytosis and contribute to tissue
damage in inflammation.
But adhesion molecules not only mediate interaction of
PMN with the environment: Upon ligand binding, several
adhesion molecules, such as integrins, transduce signals into
the cell that control adhesion-related processes, including
firm attachment and spreading and, moreover, contribute to
the activation of cellular functions (3). Thus integrins as well
as other adhesion molecules integrate ligand-dependent, i.e.,
site-specific, and signaling functions at the molecular level.
Early studies revealed that β2-integrins initiate intracellular
signal transduction processes and serve as costimulators,
e.g., upon activation of PMN by soluble mediators such as
TNF-α (9). This functional cooperation between locally
released soluble mediators and integrins provides a site-specific extracellular signal pattern and may help to control
PMN activation in inflammation. Tissue cells in inflamed
areas are known to upregulate ICAM-1, the counterreceptor
for β2-integrins, which allows adhesive interaction between
tissue cells and emigrated PMN. Since β2-integrin engagement induces and/or promotes several biological responses
of PMN, including degranulation and production of reactive
oxygen metabolites, this may increase the efficiency of host
defense. By precisely directing the destructive material to the
target area, i.e., an injured tissue cell, this mechanism prevents the uncontrolled release of the histotoxic contents of
PMN that could otherwise result in excessive tissue damage.
The engagement of β2-integrins upon costimulation by TNF-α
even triggers the activation of apoptosis, the programmed cell
death, of human PMN (14). Thus integrins not only contribute
to the control of PMN recruitment from the circulation and to
the ordered activation of their defense functions in the tissue
but also mediate their final elimination. Since apoptotic PMN
are specifically recognized and engulfed by macrophages
and tissue cells such as fibroblasts, apoptosis of PMN is currently discussed as a key mechanism that allows the resolution of acute inflammation.