title: The role of selectins and integrins in adenovirus vector-induced neutrophil recruitment to the liver.
abstract: Adenovirus vectors for human gene therapy induce early host inflammatory responses in transduced tissues that limit gene transfer efficiency and can result in significant morbidity. The present study aimed to elucidate the cellular mechanisms underlying the acute inflammation induced by adenovirus vectors in the liver. Leukocyte rolling and adhesion in response to an intravenously administered adenovirus vector was examined by intravital microscopy in mouse liver. Adenovirus vectors significantly increased leukocyte rolling and adhesion in the postsinusoidal venules within minutes of transduction. Unlike other inflammatory states in the liver, no leukocyte retention was seen in the sinusoids in response to adenovirus vector administration. Inhibition of P-selectin, alpha(4)-integrin, and E-selectin was necessary to completely block leukocyte rolling and subsequent adhesion. The administration of an anti-alpha(4)-integrin antibody alone significantly reduced leukocyte adhesion. In contrast, adenovirus vector-induced leukocyte adhesion was unchanged in CD18-knockout mice. Depletion of circulating neutrophils eliminated leukocyte rolling and adhesion in response to adenovirus vector transduction in the liver. In conclusion, adenovirus vectors induce rapid neutrophil-mediated inflammation in the post-sinusoidal venules by selectins and alpha(4)-integrin but surprisingly not by CD18.
authors.affiliation: Gastrointestinal Research Group, Department of Medicine, University of Calgary, Calgary, Canada.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Muruve
authors.forename: Robert G
authors.initials: RG
authors.lastname: Collins
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Lee
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D019040:E-Selectin / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D005822:Genetic Vectors; D006505:Hepatitis / Q000209:etiology; D006801:Humans; D007249:Inflammation / Q000209:etiology; D039441:Integrin alpha4 / Q000276:immunology; D016023:Integrins / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D019007:P-Selectin / Q000276:immunology; D019087:Selectins / Q000276:immunology*
chemical_list: D018821:CD18 Antigens; D019040:E-Selectin; D016023:Integrins; D019007:P-Selectin; D019087:Selectins; D039441:Integrin alpha4