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

II. Neutrophil Functions
333
Selectins Chemoattractants Integrins
LAD-2
LAD-1
1. Capture & Rolling
2°
2. Activation
3. Firm adhesion
4. Transmigration
1°
FIGURE 11-2 Multistep process of neutrophil effector functions. Neutrophils in flowing blood initially accumulate along the
vascular endothelium by direct (1 ° ) or indirect (2 ° ) capture. The tethered neutrophils then roll and upon chemoattractant recognition
become activated. This leads to firm adhesion and transendothelial cell migration. Upon entering the underlying tissues,
neutrophils phagocytize bacterial pathogens, which induces their programmed cell death (apoptosis). Eventually, the apoptotic
neutrophils are recognized and engulfed by macrophages to down-regulate the inflammatory response. Additionally, this figure
depicts the site of classical leukocyte adhesion deficiency (LAD-1), a deficiency of CD18, and LAD-2, a defect in the selectinmediated
adhesion.
The selectins are type I integral membrane proteins composed
of distinct tandem protein domains. At the aminoterminus
is a C-type (Ca 2 -dependent) lectin domain.
Following this is a single epidermal growth factor (EGF)-
like domain, followed by a series of short-consensus-repeat
(SCR) domains. Next are a transmembrane domain and
a short cytoplasmic region. The genes for the selectins are
arranged in tandem on chromosome 1 for both mouse and
human, indicating that they arose by gene-duplication
(Watson et al. , 1990 ). Selectin ligands are carbohydrate in
nature, and the lectin domain of the selectins is responsible
for ligand specificity and recognition ( Weis et al. , 1998 ) .
E-selectin expression is induced on most cultured endothelium
as well as most postcapillary endothelium in vivo
by a number of inflammatory mediators (Bevilacqua et al. ,
1989). Induction of E-selectin by cytokines occurs exclusively
at the transcriptional level. E-selectin mRNA is first
detectable approximately 2 h after initial exposure of endothelial
cells to cytokine. In cultured endothelium, E-selectin
expression peaks in 4 to 8h, and subsequently declines even
in the continued presence of the cytokine. In vivo , however,
E-selectin can be chronically expressed at sites of inflammation,
especially in the skin ( Ley and Kansas, 2004 ).
P-selectin is expressed on both activated platelets and
activated endothelium. Unlike E-selectin, P-selectin is
expressed in the Weibel-Palade bodies of endothelial cells
as well as the α -granules of platelets ( Bonfanti et al. , 1989 ;
McEver et al. , 1989 ). Exposure of either of these two cell
types to various stimuli induces rapid (seconds to minutes)
fusion of the P-selectin-containing granules with the outer
membrane of the cell, exposing P-selectin at the cell surface.
In the case of endothelial cells, histamine released
from tissue mast cells in response to an inflammatory insult
is one of the physiological inducers of rapid P-selectin
expression. Interestingly, P-selectin-deficient mice have a
defect in leukocyte rolling immediately following tissue
exteriorization, as determined by intravital microscopy, and
neutrophil recruitment into inflammatory lesions is delayed
by about 2h ( Mayadas et al. , 1993 ). In addition to its rapid
surface expression, P-selectin is also transcriptionally
induced ( Weller et al. , 1992 ). Moreover, P-selectin can be
chronically expressed at sites of long-standing inflammation,
such as atherosclerotic vessels, rheumatoid arthritis,
and psoriasis ( Grober et al. , 1993 ; Johnson-Tidey et al. ,
1994 ; Terajima et al. , 1998 ).
Neutrophils uniformly and constitutively express
L-selectin. This selectin arguably plays the broadest and
most significant role of the family members in neutrophil
accumulation on the endothelium as it mediates both direct
and indirect capture. In an assortment of inflammatory
models, leukocyte accumulation along the microvasculature
and recruitment into the tissue were greatly reduced ( 60%
to 85%) upon blocking L-selectin function with antibodies
or in L-selectin-deficient mice ( Davenpeck et al. , 1997 ;