Severe inflammatory defect and reduced viability in CD18 and E-selectin double-mutant mice.
CD18-deficient mice (CD18(-/-) mice) have a severe leukocyte recruitment defect in some organs, and no detectable defect in other models. Mice lacking E-selectin (CD62E(-/-) mice) have either no defect or a mild defect of neutrophil infiltration, depending on the model. CD18(-/-)CD62E(-/-), but not CD18(-/-)CD62P(-/-), mice generated by crossbreeding failed to thrive, reaching a maximum body weight of 10-15 grams. To explore the mechanisms underlying reduced viability, we investigated lethally irradiated CD62E(-/-) mice that were reconstituted with CD18(-/-) bone marrow. These mice, but not single-mutant controls, showed tenfold-increased rolling velocities in a TNF-alpha-induced model of inflammation. Leukocyte adhesion efficiency in CD18(-/-)CD62E(-/-) mice was reduced by 95%, and hematopoiesis was drastically altered, including severe bone marrow and blood neutrophilia and elevated G-CSF and GM-CSF levels. The greatly reduced viability of CD18(-/-)CD62E(-/-) mice appears to result from an inability to mount an adequate inflammatory response. Our data show that cooperation between E-selectin and CD18 integrins is necessary for neutrophil recruitment and that alternative adhesion pathways cannot compensate for the loss of these molecules.
Forlow
S B
SB
Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
White
E J
EJ
Barlow
S C
SC
Feldman
S H
SH
Lu
H
H
Bagby
G J
GJ
Beaudet
A L
AL
Bullard
D C
DC
Ley
K
K
D000818:Animals; D001835:Body Weight; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018821:CD18 Antigens / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D019040:E-Selectin / Q000235:genetics / Q000276:immunology*; D005183:Failure to Thrive; D005260:Female; D017353:Gene Deletion; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D006439:Hemodynamics; D007249:Inflammation / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D007958:Leukocyte Count; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010641:Phenotype; D012867:Skin / Q000473:pathology
D018821:CD18 Antigens; D019040:E-Selectin; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor