Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids.
Adhesion molecules known to be important for neutrophil recruitment in many other organs are not involved in recruitment of neutrophils into the sinusoids of the liver. The prevailing view is that neutrophils become physically trapped in inflamed liver sinusoids. In this study, we used a biopanning approach to identify hyaluronan (HA) as disproportionately expressed in the liver versus other organs under both basal and inflammatory conditions. Spinning disk intravital microscopy revealed that constitutive HA expression was restricted to liver sinusoids. Blocking CD44-HA interactions reduced neutrophil adhesion in the sinusoids of endotoxemic mice, with no effect on rolling or adhesion in postsinusoidal venules. Neutrophil but not endothelial CD44 was required for adhesion in sinusoids, yet neutrophil CD44 avidity for HA did not increase significantly in endotoxemia. Instead, activation of CD44-HA engagement via qualitative modification of HA was demonstrated by a dramatic induction of serum-derived HA-associated protein in sinusoids in response to lipopolysaccharide (LPS). LPS-induced hepatic injury was significantly reduced by blocking CD44-HA interactions. Administration of anti-CD44 antibody 4 hours after LPS rapidly detached adherent neutrophils in sinusoids and improved sinusoidal perfusion in endotoxemic mice, revealing CD44 as a potential therapeutic target in systemic inflammatory responses involving the liver.
McDonald
Braedon
B
Immunology Research Group, Department of Physiology and Biophysics, Institute of Infection, Immunity and Inflammation, University of Calgary, Alberta T2N 4N1, Canada.
McAvoy
Erin F
EF
Lam
Florence
F
Gill
Varinder
V
de la Motte
Carol
C
Savani
Rashmin C
RC
Kubes
Paul
P
D000818:Animals; D000911:Antibodies, Monoclonal; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D019446:Endotoxemia / Q000276:immunology; D016326:Extracellular Matrix Proteins / Q000276:immunology; D018960:Hyaluronan Receptors / Q000276:immunology*; D006820:Hyaluronic Acid / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000033:anatomy & histology* / Q000098:blood supply / Q000473:pathology*; D008107:Liver Diseases / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology*; D014699:Venules / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D008070:Lipopolysaccharides; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid