Lipopolysaccharide-induced leukocyte-endothelial cell interactions: a role for CD14 versus toll-like receptor 4 within microvessels.
The objective of this study was to systematically assess leukocyte-endothelial cell interactions in vivo in response to LPS in CD14-deficient (CD14(-/-)) and Toll-like receptor 4-deficient (TLR4(d); C3H/HeJ) mice. Local injection of LPS (0.05 micro g/kg) into muscle at a concentration that did not cause systemic effects produced a significant reduction in the speed with which leukocytes roll and a substantial increase in leukocyte adhesion and emigration 4 h postinjection. There was no response to LPS in the muscle microvasculature of CD14(-/-) mice or TLR4(d) animals. Systemic LPS induced leukopenia and significant sequestration of neutrophils in lungs in wild-type mice but not in CD14(-/-) or TLR4(d) mice. P-selectin expression was examined in numerous mouse organs using a dual radiolabeling mAb technique. The results revealed a 20- to 50-fold increase in P-selectin expression in response to LPS in all wild-type tissues examined but no response in any TLR4(d) tissues. Surprisingly, there was consistently a partial, significant increase in P-selectin expression in numerous microvasculatures including skin and pancreas, but no increase in P-selectin was detected in lung, muscle, and other organs in CD14(-/-) mice in response to LPS. Next, the skin and muscle microcirculation were visualized using intravital microscopy after systemic LPS treatment, and the results confirmed a CD14-independent mechanism of leukocyte sequestration in skin but not muscle. In summary, our results suggest that the LPS-induced leukocyte sequestration to some tissues is entirely dependent on both CD14 and TLR4 but there are CD14-independent, TLR4-dependent endothelial cell responses in some microvascular beds.
Andonegui
Graciela
G
Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Canada.
Goyert
Sanna M
SM
Kubes
Paul
P
D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D029721:Drosophila Proteins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply; D019007:P-Selectin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000098:blood supply; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D019007:P-Selectin; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors