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 m/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 (m/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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