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 (Jung
and Ley, 1999; Jung
et al., 1998; Kunkel
and Ley, 1996). This rolling requires the expression of E-selectin
on endothelial cells (Jung
and Ley, 1999; Kunkel
and Ley, 1996) and CD18 integrins on
the rolling leukocytes (Jung
et al., 1998a) and has been termed "slow rolling" to distinguish it
from the much faster rolling without cytokine stimulation. Slow rolling
can be reproduced in vitro on substrates of E-selectin (Lawrence
and Springer, 1993) and, at equivalent site densities, P-selectin
(Lawrence
and Springer, 1991). This suggests that 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.
Current estimates of typical rolling velocities under different conditions
in vivo are presented in the table below.
The transit time through the microcirculation and, more specifically,
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 (Jung
et al., 1998a). 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 (Kunkel et al., 2000). 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 (Scharffetter-Kochanek
et al., 1998).
Estimates of typical leukocyte rolling velocities in mouse cremaster venules
(µm/s), based on Jung
et al., 1996, Kunkel
and Ley, 1996, Jung
et al., 1998 b, Jung
and Ley, 1999.
| Mouse Type | Trauma | 2 hours TNF- |
6 hours TNF- |
|
| L-selectin | E/P-/- | 120 | No rolling | 19 |
| P-selectin | L/E-/- | 40 | 15 | 16 |
| E-selectin | L/P-/- | No rolling | 4 | 5 |
| 4 integrin |
E/L/P-/- | No rolling | No Rolling | 14 |
| L,P,E,4 |
Wild-type | 43 | 5 | 12 |
Click on the picture above to see the activation of slow rolling.
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