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Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment
S D Robinson1, P S Frenette, H Rayburn
1Howard Hughes Medical Institute, Department of Biology, 77 Massachusetts Avenue, Building E17, Room 227, Cambridge, MA 02139, USA.
Abstract:
We extend our previous analyses of mice deficient in selectins by describing the generation and comparative phenotype of mice lacking one, two, or three selectins after sequential ablation of the murine genes encoding P-, E-, and L-selectins. All mice deficient in selectins are viable and fertile as homozygotes. However, mice missing both P- and E-selectins (PE(-/-)), and mice missing all three selectins (ELP(-/-)) develop mucocutaneous infections that eventually lead to death. Mice deficient in multiple selectins display varying degrees of leukocytosis, resulting in part from alterations in leukocyte rolling and recruitment. PE(-/-) mice, ELP(-/-) mice, and mice missing both P- and L-selectins (PL(-/-)) show drastic reductions in leukocyte rolling and in extravasation of neutrophils in thioglycollate-induced peritonitis. In a separate inflammatory model (ragweed-induced peritoneal eosinophilia), we demonstrate P-selectin to be both necessary and sufficient for the recruitment of eosinophils. The phenotype of mice missing both E- and L-selectins (EL(-/-)) is less severe than those seen in the other double knockouts. Comparisons among the double knockouts suggest that P-selectin normally cooperates with both E- and L-selectins. Our results indicate a preeminent role for P-selectin in regulating leukocyte behavior in mice. Data from the ELP(-/-) mice indicate, however, that all three selectins are important to leukocyte homeostasis and efficient neutrophil recruitment.
Insights
Mice lacking P-, E-, and L-selectins show impaired leukocyte function and survival. P-selectin plays a key role in leukocyte recruitment, but all three selectins are vital for immune homeostasis.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Selectins mediate leukocyte adhesion and trafficking, crucial processes in immune responses.
- Previous studies analyzed mice with single selectin deficiencies; this study investigates combined deficiencies.
Purpose of the Study:
- To generate and characterize mice with sequential genetic ablation of P-, E-, and L-selectins.
- To compare the phenotypes of mice lacking one, two, or all three selectins.
- To elucidate the specific roles of each selectin and their cooperative functions in leukocyte homeostasis and inflammation.
Main Methods:
- Sequential genetic ablation of murine genes encoding P-, E-, and L-selectins.
- Phenotypic analysis of mice with single, double, and triple selectin deficiencies.
- Assessment of leukocyte rolling, recruitment, and extravasation in inflammatory models (thioglycollate-induced peritonitis, ragweed-induced peritoneal eosinophilia).
Main Results:
- Mice lacking P- and E-selectins (PE(-/-)) or all three (ELP(-/-)) developed fatal mucocutaneous infections.
- Multiple selectin deficiencies resulted in varying degrees of leukocytosis and impaired leukocyte rolling and neutrophil recruitment.
- P-selectin was essential for eosinophil recruitment in a ragweed-induced model.
- Double knockouts revealed cooperative roles between P-selectin and E- or L-selectins.
Conclusions:
- P-selectin plays a preeminent role in regulating leukocyte behavior and recruitment.
- While P-selectin is critical, E-, L-, and P-selectins collectively are important for leukocyte homeostasis and efficient neutrophil recruitment.
- Combined deficiencies in selectins can lead to severe phenotypes, including susceptibility to infection, highlighting their essential combined functions.