title: The role of alpha(4) and LFA-1 integrins in selectin-independent monocyte and neutrophil migration to joints of rats with adjuvant arthritis.
abstract: Monocytes and neutrophils are chronically recruited to joints in rheumatoid arthritis. In the joints of rats with adjuvant arthritis, this is mediated, in part, by selectin-dependent and selectin-independent mechanisms. To define the selectin-independent mechanisms, (51)Cr-labeled blood monocytes, (111)In-labeled neutrophils and function blocking mAb to the selectins and integrins were utilized. Integrins contributed to the selectin-independent monocyte migration to arthritic joints with 58-70% inhibition of this recruitment by anti-alpha(4) or anti-LFA-1 mAb, relative to selectin blockade alone. alpha(4) plus P-selectin blockade was as effective as combined blockade of alpha(4), P-, E- and L-selectin, mediating approximately 83% of the overall monocyte migration to the joints. In contrast, LFA-1 was the predominant selectin-independent mechanism for neutrophil recruitment to the joints. LFA-1 together with P-selectin had essential roles in the talar joint. In dermal inflammation in the arthritic rats, LFA-1 accounted for most (69%) of the selectin-independent monocyte migration to the chemoattractant C5a(desArg) (zymosan-activated serum), whereas LFA-1 and Mac-1 both contributed to selectin-independent neutrophil recruitment to C5a(desArg). alpha(4) integrin and P-selectin in concert mediated monocyte recruitment to lipopolysaccharide and IFN-gamma lesions (81%). Thus: (1) either alpha(4) or LFA-1 can mediate monocyte migration to arthritic joints in the absence of selectin function and alpha(4) together with P-selectin is particularly important; (2) LFA-1 is the predominant mechanism of selectin-independent migration of neutrophils to inflamed joints; and (3) in arthritic rats, selectin-independent migration of monocytes and neutrophils to dermal inflammation is mediated by alpha(4) or LFA-1 or both LFA-1 and Mac-1, depending on the leukocyte type, and inflammatory stimulus.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3J 3G9, Canada.
authors.forename: U
authors.initials: U
authors.lastname: Birner
authors.forename: T B
authors.initials: TB
authors.lastname: Issekutz
authors.forename: U
authors.initials: U
authors.lastname: Walter
authors.forename: A C
authors.initials: AC
authors.lastname: Issekutz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000503:physiopathology; D002465:Cell Movement; D003872:Dermatitis / Q000276:immunology; D039441:Integrin alpha4; D007596:Joints / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D019007:P-Selectin / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D015703:Antigens, CD; D016169:Lymphocyte Function-Associated Antigen-1; D019007:P-Selectin; D039441:Integrin alpha4