Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 11 Neutrophil Function
Jung et al. , 1998 ; Kanwar et al. , 1999 ; Ley et al. , 1993 ;
Tedder et al. , 1995 ; Von Andrian et al. , 1991, 1992, 1993 ).
Consistent with L-selectin’s broad role in neutrophil
recruitment, it is tightly regulated. For instance, neutrophils
down-regulate L-selectin expression by ectodomain
proteolysis (shedding) in a very efficient and rapid manner
upon their stimulation by cytokines and chemoattractants
( Alexander et al. , 2000 ; Kishimoto et al. , 1989 ;
Rizoli et al. , 1999 ; Walcheck et al. , 1996 ). Studies performed
in vitro and in vivo indicate that L-selectin shedding
affects leukocyte adhesiveness and recruitment
( Hafezi-Moghadam and Ley, 1999 ; Venturi et al. , 2003 ,
Walcheck et al. , 1996 ). In addition, homeostatic L-selectin
shedding maintains high levels of soluble L-selectin in the
serum ( 1 to 3 μ g/ml) ( Kishimoto et al. , 1995 ; Palecanda
et al. , 1992 ), which is functional and can diminish leukocyte-endothelium
interactions. Soluble L-selectin may
thus serve as an adhesion buffer to suppress neutrophil
accumulation below a certain inflammatory threshold.
Interestingly, a reduced level of serum L-selectin correlates
with susceptibility to inflammatory disease ( Donnelly
et al. , 1994 ; Seidelin et al. , 2002 ). TNF- α converting
enzyme (TACE or ADAM17) appears to be a key sheddase
of L-selectin upon overt cell activation.
The selectin family of adhesion proteins is highly
selective lectins that recognize specific glycan structures
displayed in most cases on an appropriate protein backbone.
The main glycoprotein ligand for P-selectin on neutrophils
is a homodimeric sialomucin designated PSGL-1
(P-selectin glycoprotein ligand-1) ( Moore et al. , 1995 ;
Sako et al. , 1993 ). PSGL-1 also serves as the primary
ligand for L-selectin during leukocyte-leukocyte facilitated
indirect neutrophil accumulation along the endothelium
( Walcheck et al. , 1996 ). Importantly, specific posttranslational
modifications of PSGL-1 are required for L- and
P-selectin recognition. PSGL-l has a tyrosine sulfate motif
at its amino-terminus, and mutational analyses have revealed
that at least one of the three tyrosines in the motif must be
sulfated for recognition ( Pouyani and Seed, 1995 ; Sako
et al. , 1995 ). In addition, a threonine residue just downstream
from the tyrosine sulfate motif must be modified by
sialylated, fucosylated oligosaccharides, such as a core 2
O-glycan terminated by sialyl Lewis X (sLe X ) ( Leppanen
et al. , 1999, 2003 ). PSGL-1 has also been reported to
function as a ligand for E-selectin ( Asa et al. , 1995 ; Sako
et al. , 1993 ). However, leukocytes derived from PSGL-l
knockout mice demonstrated no obvious defect in rolling
on E-selectin ( Yang et al. , 1999 ). Altogether, various studies
suggest that PSGL-1 expression by neutrophils is not
as critical for E-selectin binding as it is for L- and P-selectin.
Indeed, other E-selectin ligands on neutrophils have
been described, including E-selectin ligand-1 (ESL-1),
glycolipids, and L-selectin ( Alon et al. , 1995 ; Steegmaier
et al. , 1995 ). In addition to recognizing its leukocyte ligand
PSGL-1, L-selectin on neutrophils also mediates their
direct accumulation on the endothelium, yet these endothelial
ligands remain poorly characterized.
4 . Chemoattractants
Chemoattractants are small soluble molecules that bind to
receptors on leukocytes causing their stimulation, polarization,
and locomotion, in part through the activation of the
integrin adhesion molecules. Leukocyte locomotion toward
higher concentrations of a chemoattractant is referred to as
chemotaxis, and this can occur in a hierarchal manner. For
instance, neutrophils become less sensitive to an initially
encountered chemoattractant gradient, allowing them to then
respond to a newly encountered chemoattractant ( Foxman
et al. , 1997, 1999 ). This process allows neutrophils to find
their ultimate target through a complex stimulant environment.
Different classes of chemoattractants include chemokines,
lipid mediators, complement factors, and other
peptides. The largest class of chemoattractants constitutes
the chemokines, a superfamily of small, secreted proteins
(8 to 10 kDa). The chemokines are structurally homologous
and are subdivided into four subfamilies based on the position
of conserved cysteine residues near the amino-terminus
of the molecules ( Rot and von Andrian, 2004 ). CXC chemokines
( α -chemokines) are characterized by the presence of
two cysteine residues that are separated by one amino acid,
CC chemokines ( β -chemokines) have two cysteine residues
that are adjacent, C chemokines have one cysteine residue
near the amino-terminus, and the CXXXC subfamily is
characterized by cysteines being separated by three amino
acids. The CC and CXC chemokines represent the largest
of the chemokine families and contain many members.
The C and CXXXC subfamilies together consist of three
members at this time. The CXC chemokines can be further
subdivided based on the presence or absence of a glutamatic
acid-lysine-arginine (ELR) sequence preceding the
CXC motif. This structural difference determines separate
functional activities of chemokines in this subfamily. CXC
chemokines that contain an ELR sequence (e.g., IL-8) are
chemotactic for neutrophils, whereas non-ELR-containing
CXC chemokines and CC chemokines appear not to be
active on neutrophils ( DeVries et al. , 1999 ). Chemokines
induce leukocyte activation and locomotion by binding to
specific G-protein-coupled cell surface receptors. Most
chemokine receptors recognize more than one chemokine,
and several chemokines can bind to more than one receptor.
However, there is receptor-ligand specificity within chemokine
subfamilies, with CXC chemokines binding exclusively
to CXC receptors and CC chemokines binding to CC
receptors ( Rot and von Andrian, 2004 ).
5 . Integrins
Integrins mediate neutrophil firm adhesion and locomotion
by interacting with ligands on cells and in the extracellular