Dermal and pulmonary inflammatory disease in E-selectin and P-selectin double-null mice is reduced in triple-selectin-null mice

In the initial phase of an inflammatory response, leukocytes; marginate and roll along the endothelial surface as a result of adhesive interactions be tween molecules on the endothelial cells and leukocytes. To evaluate the ro le of the 3 selectins (E, L, and P) in leukocyte rolling and emigration, a null mutation for L-selectin was introduced into previously described embry onic 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-selec tin, L-selectin, and P-selectin [E/L/P] triple mutants). Triple-selectin ho mozygous mutant mice are viable and fertile and only rarely develop the sev ere 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 periph eral neutrophils. Pathological studies revealed moderate cervical lymphaden opathy and lymphoplasmacytic infiltrate, but these were less extensive than in E/P double-mutant mice. Neutrophil emigration during thioglycolate-indu ced peritonitis was significantly reduced at 4, 8, and 24 hours (35%, 65%, and 46% of wild-type values, respectively). Intravital microscopy of the cr emaster muscle revealed almost no rolling at times up to 6 hours after exte riorization, with or without addition of tumor necrosis factor alpha. The s mall amount of residual rolling was dependent on alpha4-integrin. The occur rence 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 infla mmatory response in E/P mutants. (C) 2001 by The American Society of Hemato logy.