title: Role of alpha4 integrin and VCAM-1 in CD18-independent neutrophil migration across mouse cardiac endothelium.
abstract: Myocardial damage due to reperfusion of ischemic tissue is caused primarily by infiltrating neutrophils. Although leukocyte beta2 integrins (CD18) play a critical role, significant neutrophil emigration persists when CD18 is neutralized or absent. This study examined the role of leukocyte beta1 integrin (alpha4) and its endothelial ligand VCAM-1 in CD18-independent neutrophil migration across cardiac endothelium. In a mouse model of myocardial ischemia and reperfusion, we show that compared with wild-type mice, neutrophil infiltration efficiency was reduced by 50% in CD18-null mice; in both types of mice, myocardial VCAM-1 staining increased after reperfusion. In wild-type mice, antibodies against CD18, ICAM-1 (an endothelial ligand for CD18), or VCAM-1 given 30 minutes before ischemia did not block neutrophil emigration at 3 hours reperfusion. Although anti-VCAM-1 attenuated neutrophil emigration by 90% in CD18-null mice, it did not diminish myocardial injury. To determine if CD18-independent neutrophil emigration was a tissue-specific response, we used isolated peripheral blood neutrophils from wild-type or CD18-null mice and showed neutrophil migration across lipopolysaccharide-activated cultured cardiac endothelium is CD18-independent, whereas migration across endothelium obtained from inferior vena cava is CD18-dependent. Consistent with our in vivo findings, migration of CD18-deficient neutrophils on cardiac endothelial monolayers is blocked by antibodies against alpha4 integrin or VCAM-1. We conclude tissue-specific differences in endothelial cells account, at least partially, for CD18-independent neutrophil infiltration in the heart.
authors.affiliation: Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, Md, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bowden
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Ding
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Donnachie
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Petersen
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Michael
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.forename: Alan R
authors.initials: AR
authors.lastname: Burns
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D018821:CD18 Antigens / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D039441:Integrin alpha4; D039041:Integrin alpha4beta1; D016167:Integrin alphaXbeta2 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D014682:Vena Cava, Inferior / Q000276:immunology / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D018821:CD18 Antigens; D039041:Integrin alpha4beta1; D016167:Integrin alphaXbeta2; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4