Adhesion molecules mediating neutrophil migration to arthritis in vivo and across endothelium and connective tissue barriers in vitro.
Neutrophils, or polymorphonuclear leukocytes (PMNLs), migrate through vascular endothelium and in connective tissue during inflammation. In rats with adjuvant arthritis, migration to joints of radiolabeled (111In) blood PMNLs was examined to define the role of specific selectin and integrin adhesion molecules in this process. Based on monoclonal antibody studies, P-selectin was required for normal PMNL migration to the joints. Although E-selectin alone was not essential, it mediated PMNL accumulation when the P-selectin mechanism was blocked. However, 30% to 40% of the PMNL accumulation was L-, P-, and E-selectin-independent. The integrins, LFA-1 and Mac-1 (CD11/CD18), and VLA-4 mediated PMNL migration to arthritic joints. However, 20% to 40% of PMNL accumulation was via CD18- and VLA-4-independent mechanisms. Human PMNL migration in vitro across unstimulated human umbilical vein endothelial cells (HUVEC), induced by C5a or IL-8, was virtually all mediated by the CD18 (beta2) integrins, LFA-1 and Mac-1. PMNL transendothelial migration was partly CD18-independent (35%) when endothelium was activated with cytokines, such as interleukin-1, and a chemotactic gradient, such as C5a, was also present. This CD18-independent migration was partially E-selectin-dependent in vitro. PMNL migration across synovial fibroblasts induced by C5a was mediated by Mac-1, VLA-4, VLA-5, and VLA-6, functioning in concert. However, up to 30% of migration was via mechanisms as yet to be defined. Thus, PMNL transendothelial and extravascular migration involves some shared, and some distinct mechanisms, as well as some yet to be identified. Defining these mechanisms may help develop therapies for controlling PMNL involvement in inflammation in the vascular and extravascular spaces.
Issekutz
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AC
Department of Pediatrics, Dalhousie University, IWK Grace Health Centre, Halifax, Nova Scotia, Canada. aissekutz@iwkgrace.ns.ca
D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D003238:Connective Tissue / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D016023:Integrins / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D019087:Selectins / Q000502:physiology
D015815:Cell Adhesion Molecules; D016023:Integrins; D019087:Selectins