title: The role of CD14 in neutrophil recruitment within the liver microcirculation during endotoxemia.
abstract: During Gram-negative sepsis and endotoxemia, CD14 is essential for the recognition of LPS by the TLR4 complex and subsequent generation of systemic inflammation. However, CD14-independent responses to LPS have been reported in vitro and in vivo in selected tissues including the skin. As the liver is a key target organ for neutrophil sequestration and inflammatory pathology during sepsis and endotoxemia, we investigated the role of CD14 in the recruitment of neutrophils into the liver in a mouse model of endotoxemia. Using dynamic in vivo imaging of the liver, we observed that neutrophil recruitment within the sinusoids and post-sinusoidal venules occurred equivalently between LPS-treated wild-type and CD14-knockout mice. Neutrophil recruitment within the liver was completely independent of CD14 regardless of whether it was expressed on cells of hematopoietic or nonhematopoietic origin or in serum as soluble CD14. Whereas CD14 expression was essential for activation of circulating neutrophils and for the development of LPS-induced systemic inflammation (pulmonary neutrophil sequestration, leukopenia, and increased serum proinflammatory cytokine levels), deficiency of CD14 did not limit the adhesion strength of neutrophils in vitro. Furthermore, wild-type and CD14-knockout mice displayed identical deposition of serum-derived hyaluronan-associated protein within liver sinusoids in response to LPS, indicating that the sinusoid-specific CD44/hyaluronan/serum-derived hyaluronan-associated protein-dependent pathway of neutrophil adhesion is activated independently of CD14. Therefore, the liver microcirculation possesses a unique CD14-independent mechanism of LPS detection and activation of neutrophil recruitment.
authors.affiliation: Immunology Research Group, Department of Physiology and Pharmacology, Snyder Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Erin F
authors.initials: EF
authors.lastname: McAvoy
authors.forename: Braedon
authors.initials: B
authors.lastname: McDonald
authors.forename: Sean A
authors.initials: SA
authors.lastname: Parsons
authors.forename: Connie H
authors.initials: CH
authors.lastname: Wong
authors.forename: Regine
authors.initials: R
authors.lastname: Landmann
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019446:Endotoxemia / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008102:Liver Circulation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000235:genetics / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine