Mice lacking E-selectin show normal numbers of rolling leukocytes but reduced leukocyte stable arrest on cytokine-activated microvascular endothelium.
OBJECTIVE
Previous work indicated that E-selectin mediates transient interactions between leukocytes and cytokine-activated endothelium in vitro. Here we examine the role of E-selectin in blood leukocyte interactions with microvascular endothelium in vivo.


METHODS
E-selectin-deficient (E-/-) mice were produced by gene targeting. The effect of this null mutation on leukocyte-endothelial interactions was determined by intravital microscopy before and 4 to 5 hours after local administration of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) in dermal microvessels with low blood flow (dorsal skin-fold chambers, intact ear skin), and after endotoxin activation in exteriorized mesenteric microvessels with higher blood flow.


RESULTS
E-/- mice were viable, fertile with normal circulating leukocyte and platelet profiles. Approximately 60% of circulating leukocytes rolled in dermal microvessels of both normal (E+/+) and E-/- mice without inflammatory stimulation. After local administration of TNF alpha, rolling increased modestly and equivalently in both genotypes. The main effect of TNF alpha was a dramatic increase in leukocyte stable adhesion and, unlike rolling, this manifestation of endothelial activation was significantly reduced in E-/- animals. This reflected fewer dermal microvessels supporting higher adhesion densities in E-/- mice, and a similar trend was observed in mesenteric microvessels.


CONCLUSIONS
E-selectin plays a previously unappreciated role in facilitating and/or mediating stable adhesion of leukocytes to inflamed microvascular endothelium.
Milstone
D S
DS
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Fukumura
D
D
Padgett
R C
RC
O'Donnell
P E
PE
Davis
V M
VM
Benavidez
O J
OJ
Monsky
W L
WL
Melder
R J
RJ
Jain
R K
RK
Gimbrone
M A
MA
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000502:physiology*; D019040:E-Selectin / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D007962:Leukocytes / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology*; D012867:Skin / Q000098:blood supply; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D019040:E-Selectin; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha