Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 95

Neutrophil migration relies on 2 main pathways: (1) phosphatidylinositol
3-kinase that is activated by interactions between chemokines and G-protein-
coupled receptors and (2) mitogen-activated protein kinase P38MAPK pathway
that dominates in chemotaxis induced by bacterial or complement chemoattractants.
Lipid and protein phosphatase and tensin homolog (PTen) that counteracts PI3K
acts for priorization of bacterial chemoattractants for neutrophil migration toward
bacterial products via phospholipase-A2 and P38MAPK [ 183 ].
In their search for bacteria, neutrophils respond to many chemotactic sub-
stances produced by macrophages, mastocytes, or serosal cells. Near the infection
site, neutrophils select chemoattractants, favoring bacterial chemoattractants (e.g.,
N formyl-methionyl-leucyl-phenalanine and complement component C5a) rather
than chemokines and leukotrienes.

3.7.3.5 Neutrophil Extravasation

Pentraxin-3 (a.k.a. TNF IP5) has both inflammatory and

anti-inflammatory effects. 74 On the one hand, cytokines and liganded Toll-like
receptors stimulate Ptx3 synthesis in endothelial cells, macrophages, and dendritic
cells, as well as Ptx3 storage in neutrophils [ 184 ]. Neutrophils secrete Ptx3 that
promotes innate immunity, as it binds to pathogens and activates complement [ 185 ].
C-terminus of Ptx3 links to the complement protein C1q, among other substances
such as P-selectin.
Inflammation relies on the recruitment of circulating cells. Rolling permits
selectin ligands and chemokine receptors on neutrophils to prime deceleration,
arrest, then extravasation. Pentraxin-3 can limit neutrophil recruitment, as it impedes
rolling on P-selectin in inflamed venules. It indeed sequesters P-selectin away from
its endothelial ligands. In summary, neutrophils rolling on P-selectin in venules at
sites of infection or injury receive signals that release paracrine regulator Ptx3 from
specific granules. Released Ptx3 binds to locally expressed P-selectin in a paracrine
manner.
Therefore, pentraxin-3 is another inhibitor of leukocyte adhesion to vascular
endothelia. The integrin ligand EGF-like repeats and discoidin-1 (I)-like domain-
containing protein EDIL3 is a matrix glycoprotein secreted by endothelial cells. 75
EDIL3 ligand inhibits adhesion of leukocytes and endothelial progenitor cells, as it

α -induced protein TNF α

74 Pentraxins constitute a superfamily of evolutionarily conserved multimeric proteins. Classic
short pentraxins include C-reactive protein and serum amyloid-P that are produced mainly in
the liver. Pentraxin-3 is a long pentraxin. Unlike classic short pentraxins that vary in sequence
and regulation among mammalian species, Ptx3 is highly conserved between mouse and man for
sequence, ligand recognition, and regulation.
75 Protein EDIL3, a.k.a. Developmental endothelial locus DEL1, connects to

β 2 - (e.g., leukocyte

α L β 2 -integrin), α V β 3 -and α V β 5 -integrins.