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Blood, 1 August 2001, Vol. 98, No. 3, pp. 727-735
IMMUNOBIOLOGY
Dermal and pulmonary inflammatory disease in E-selectin and
P-selectin double-null mice is reduced in
triple-selectin-null mice
Robert G. Collins,
Unsu Jung,
Maricela Ramirez,
Daniel C. Bullard,
M. John Hicks,
C. Wayne Smith,
Klaus Ley, and
Arthur L. Beaudet
From the Departments of Molecular and Human Genetics,
Pediatrics, and Pathology, Baylor College of Medicine, Houston, TX; the
Department of Biomedical Engineering, University of Virginia Health
Sciences Center, Charlottesville, VA; and the Department of Comparative
Medicine, University of Alabama-Birmingham, Birmingham, AL.
In the initial phase of an inflammatory response, leukocytes
marginate and roll along the endothelial surface as a result of
adhesive interactions between molecules on the endothelial cells and
leukocytes. To evaluate the role of the 3 selectins (E, L, and P) in
leukocyte rolling and emigration, a null mutation for L-selectin was
introduced into previously described embryonic stem cells with null
mutations in the genes for both E-selectin and P-selectin (E/P
double mutants) to produce triple-selectin-null mice (E-selectin,
L-selectin, and P-selectin [E/L/P] triple mutants). Triple-selectin homozygous mutant mice are viable and fertile and only
rarely develop the severe mucocutaneous infections or pulmonary
inflammation characteristic of E/P double-mutant mice. Surface
expression of L-selectin was undetectable in triple-mutant mice on
fluorescence-activated cell-sorter analysis of peripheral neutrophils.
Pathological studies revealed moderate cervical lymphadenopathy and
lymphoplasmacytic infiltrate, but these were less extensive than in E/P
double-mutant mice. Neutrophil emigration during thioglycolate-induced peritonitis was significantly reduced at 4, 8, and 24 hours (35%, 65%, and 46% of wild-type values, respectively). Intravital
microscopy of the cremaster muscle revealed almost no rolling at times
up to 6 hours after exteriorization, with or without addition of tumor
necrosis factor  . The small amount of residual rolling was dependent
on 4-integrin. The occurrence of skin and pulmonary disease in E/P double-mutant mice but not E/L/P triple-mutant mice
suggests that deficiency of L-selectin alters the inflammatory response
in E/P mutants.
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