Severe inflammatory defect and reduced viability in CD18 and E-selectin double-mutant mice
S.B. Forlow, … , D.C. Bullard, K. Ley
S.B. Forlow, … , D.C. Bullard, K. Ley
Published December 15, 2000
Citation Information: J Clin Invest. 2000;106(12):1457-1466. https://doi.org/10.1172/JCI10555.
View: Text | PDF
Article

Severe inflammatory defect and reduced viability in CD18 and E-selectin double-mutant mice

Abstract

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-α–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.

Authors

S.B. Forlow, E.J. White, S.C. Barlow, S.H. Feldman, H. Lu, G.J. Bagby, A.L. Beaudet, D.C. Bullard, K. Ley

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
Effect of shear rate on leukocyte rolling velocity distributions in TNF-...
Effect of shear rate on leukocyte rolling velocity distributions in TNF-α–treated cremaster muscle venules of wild-type, CD62E–/–, CD18–/–, and CD18–/–CD62E–/– mice. Cumulative frequency curves of leukocyte rolling velocities in shear-rate ranges of 100–400 s–1 (thin dotted line), 400–700 s–1 (thin solid line), and 700–1500 s–1 (thick solid line). All leukocytes rolling at velocities over 140 μm/s are represented by last data point. Median rolling velocity for each shear-rate range is indicated by vertical lines. Inset shows rolling velocities of three leukocytes rolling over a 200-μm distance in a venule of a wild-type mouse (closed circles, wall shear rate 754 s–1) and of three leukocytes rolling in a CD18–/–CD62E–/– mouse (open circles, wall shear rate 729 s–1).