Topic 2 lecture note..

so they may stick and roll along the venular endothelium. In vitro, isolated human
granulocytes have been shown to roll on purified P-selectin using flow chamber systems.
L-selectin and E-selectin also take part in the rolling process. When P-selectin is absent,
trauma-induced rolling becomes L-selectin dependent, but the average leukocyte rolling
velocity is three to five times faster in this case. This suggests that L-selectin is much less
efficient than P-selectin in mediating the rolling process. However, L-selectin is
necessary for the normal inflammatory response in capturing leukocytes and initiating
rolling. An apparent redundancy exists between P- and E-selectin in mediating leukocyte
rolling on cytokine-activated endothelium. E-selectin is thought to be responsible for
slow rolling interactions, and possibly the initiation of firm adhesion.
Slow rolling
After induction of inflammation by injection of a pro-inflammatory cytokine like TNF-,
leukocyte rolling velocity drops dramatically to an average between 5 and 10 µm/s. This
rolling requires the expression of E-selectin on endothelial cells and CD18 integrins on
the rolling leukocytes, and has been termed "slow rolling" to distinguish it from the much
faster rolling without cytokine stimulation. Slow rolling is not based on a unique property
of E-selectin, but the expression of E-selectin and/or its ligands appears to be sufficiently
high in vivo to support slow rolling. The contact time during which the leukocyte is in
close proximity with the endothelium, appears to be a key parameter in determining the
success of the recruitment process as reflected in firm adhesion. The important role of
leukocyte transit time appears to be related to chemokines that are presented on the
endothelial surface and are likely to be accessible to the leukocyte as long as it rolls. This
is supported by tracking studies, in which individual rolling leukocytes were found to
slow down systematically before becoming firmly adherent. Rolling leukocytes are likely
to be activated by surface-bound chemoattractants and through adhesion molecule-based
signaling. It is also possible that the velocity of rolling may have an effect independent of
transit time, because secondary binding events (e.g., 2 integrin-mediated) may not be
able to form unless the leukocyte spends a certain amount of time in a position favorable
for bond formation. Although slow rolling makes leukocyte recruitment much more
efficient, it is not strictly required, because high concentrations of chemoattractants can
also arrest fast-rolling leukocytes. Chemokines activate integrins resulting in firm
adhesion of leukocytes to the vascular wall.
Firm adhesion
It is thought that most if not all leukocytes adhere only after having rolled. Several
studies suggest that direct adhesion (from the free-flowing leukocyte pool) is extremely
rare. E-selectin participates in the conversion of rolling to firm adhesion. E-selectin
deficient mice have a reduced number of firmly adherent leukocytes in response to local
chemoattractant or cytokine stimulation.
Interfering with CD18 integrin function is one of the most efficient ways to curb
leukocyte recruitment in many forms of experimental inflammation. Although the
response to exogenous chemoattractant is drastically reduced when CD18 is absent or not
functional, cytokine treatment still yields a robust inflammatory response in gene-