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.
Neutrophil migration from blood into inflamed tissues is mediated by adhesion molecules on neutrophils and on vascular endothelium. It was previously shown that the integrins VLA-4 and CD11/CD18 in combination mediate 70-80% of neutrophil recruitment to arthritic joints of rats. To investigate if the remaining recruitment involves the selectins, the effect of adhesion-blocking monoclonal antibodies (mAb) to each of the selectins (E-, P and L-), in combination with mAb to VLA-4 and CD18, on the migration of radiolabeled neutrophils to joints of rats with adjuvant arthritis was examined. Blocking P-selectin inhibited neutrophil accumulation in hindlimb joints by 40% whereas mAb to P- and E-selectin together inhibited the accumulation in all joints by 60% relative to anti-VLA-4 plus anti-CD18 treatment alone. Overall there was 90% inhibition relative to arthritic controls. Blocking E- or L-selectin alone or together had no effect. Our results demonstrate that P-selectin in particular and in concert with E-selectin are required for the VLA-4- and CD18-independent migration of neutrophils to sites of chronic arthritis in the rat.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.