Biomedical Engineering Reference
In-Depth Information
modulated by site- and environment-specii c stimuli. Integrin activation through
the receptors associated with these second stimuli and followed by a consequent
change of integrin expression and clustering is known as 'inside-out signaling.
It becomes increasingly clear that the cooperation of inside-out and outside-in
signaling events determines the ef ects of a particular leukocyte type and subset.
ADHESION MOLECULES ON NEUTROPHILS
Neutrophils are rapidly mobilized to the site of inl ammation. An activated
neutrophil manifests a number of functional responses as spreading, transmigration,
phagocytosis, superoxide production, and degranulation. Neutrophils express
PSGL-1, L-selectin and
β
2
-integrins,
α
L
β
2
,
α
M
β
2
, and
α
X
β
2
, as well as low levels
of
α
4
β
1
. Neutrophil interaction with endothelium involves multiple molecules
including P-selectin glycoprotein ligand-1 (PSGL-1), L-selectin, G-protein coupled
receptors, and integrins leading to activation of dif erent intracellular pathways.
Expression of L-selectin and PSGL-1 regulates mobilization and capture of
neutrophils by endothelium in conditions of share stress. Neutrophil is the only
leukocyte type expressing PSGL-1. PSGL-1 is located in lipid rat s on microvilli of
leukocytes serving as a ligand to L-selectin and P-selectin. Elimination of PSGL-1
gene reduces the number of neutrophils interacting with endothelium, alters
rolling velocity and results in poor recruitment of neutrophils to the inl ammation
site. Ligation of PSGL-1 results in phosphorylation of its cytoplasmic tail and
mobilization of the proteins of ezrin/radixin/moesin family, functioning as a
link between plasma membrane and the actin cytoskeleton. Additionally, the
N-terminal region of ezrin/radixin/moesin proteins interacts with spleen tyrosine
kinase (Syk) regulating
β
1
activation (inside-out signaling).
Activation of neutrophils results in a rapid shedding of L-selectin from the
cell surface by disintegrins of ADAM family (Ivetic and Ridley 2004). Blocking of
L-selectin shedding
in vivo
leads to an increase in neutrophil arrest and reduces
neutrophil rolling velocity. Cross-linking of L-selectin by antibodies results in
increased intracellular Ca
+2
levels, Scr-dependent tyrosine phosphorylation and
activation of MAP-kinases followed by O
2
-radicals production.
Slow rolling of neutrophils along the inl amed vessel wall is mediated by
β
2
-integrins
α
L
α
L
β
2
and
α
M
β
2
. Ligation of PSGL-1 and exposure to chemokines
induces activation of
β
2
-integrins. Binding of paxillin to the cytoplasmic tail of
the
α
-integrin results in the dissociation of
α
and
β
subunits, conformational
changes of the
β
2
-integrin I domain and the exposure of high ai nity binding sites
for its ligands. h is leads to an ei cient conversion from rolling to i rm adhesion
of neutrophils. During neutrophil migration,
α
L
β
2
forms ring-like clusters at
the neutrophil-endothelial junction.
β
2
is stored in neutrophil granuli and
readily released following activation. In addition to ICAM-1,
α
M
β
2
has several
other ligands including bacterial and fungal glycoproteins, heparin, i brinogen,
coagulation factor X and complement C3.
α
M
