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Department of Biomedical Engineering, University of Virginia Health Sciences Center, Charlottesville, VA 22908
Leukocyte rolling along the walls of inflamed venules precedes
their adhesion during inflammation. Rolling leukocytes are thought to
arrest by engaging ß2 integrins following cellular
activation. In vitro studies suggest that chemoattractants may
instantaneously activate and arrest rolling leukocytes. However, how
leukocytes stop rolling and become adherent in inflamed venules in vivo
has remained rather mysterious. In this paper we use a novel method of
tracking individual leukocytes through the microcirculation to show
that rolling neutrophils become progressively activated while rolling
down the venular tree. On average, leukocytes in wild-type mice roll
for 86 s (and cover 270 µm) before becoming adherent with an
efficiency around 90%. These rolling leukocytes exhibit a gradual
ß2 integrin-dependent decrease in rolling velocity that
correlates with an increase in intracellular free calcium concentration
before arrest. Similar tracking analyses in gene-targeted mice
demonstrate that the arrest of rolling leukocytes is very rare when
ß2 integrins are absent or blocked by a mAb. Arrest is
50% less efficient in the absence of E-selectin. These data suggest
a model of leukocyte recruitment in which ß2 integrins
play a critical role in stabilizing leukocyte rolling during a
protracted cellular activation period before arrest and firm
adhesion.
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