Shedding of Large Functionally Active CD11/CD18 Integrin Complexes from Leukocyte Membranes during Synovial Inflammation Distinguishes Three Types of Arthritis through Differential Epitope Exposure

Abstract

CD18 integrins are adhesion molecules expressed on the cell surface of leukocytes and play a central role in the molecular mechanisms supporting leukocyte migration to zones of inflammation. Recently, it was discovered that CD11a/CD18 is shed from the leukocyte surface in models of inflammation. In this study, we show that shedding of human CD11/CD18 complexes is a part of synovial inflammation in rheumatoid arthritis and spondyloarthritis but not in osteoarthritis. In vivo and in vitro data suggest that the shedding is driven by TNF-α, which links the process to central events in the inflammatory response. The shed complexes contain multiple heterodimers of CD11/CD18, are variable in size, and differ according to the type of synovial inflammation. Furthermore, the differential structures determine the avidity of binding of the complexes to the ICAM-1. With the estimated concentrations of CD11/CD18 in plasma and synovial fluid a significant coverage of binding sites in ICAM-1 for CD18 integrins is expected. Based on cell adhesion experiments in vitro, we hypothesize that the large soluble complexes of CD11/CD18 act in vivo to buffer leukocyte adhesion by competing with the membrane-bound receptors for ICAM-1 binding sites. As reported here for synovial inflammation changes in the concentration or structure of these complexes should be considered as likely contributors to disease activity.

Metalloproteinase-mediated Shedding of Integrin β2 Promotes Macrophage Efflux from Inflammatory Sites

“…We show that peritoneal levels of soluble integrin ␤2 are elevated both at the time of initial exiting of resident macrophages and during the slow resolution phase. As shown by studies of synovial fluids (12), the release of soluble integrin ␤2 may buffer leukocyte adhesion thus further limiting leukocyte influx and/or activation. In addition, soluble complexes may retain signaling capabilities.…”

“…In human blister fluid, truncated ectodomains of ␣L␤2 (LFA-1) were detected, and neutrophils and monocytes showed a loss of cell surface ␣L␤2 (10). More recently, shedding of integrin ␤2 complexed with different ␣ subunits was shown to be a part of synovial inflammation in rheumatoid arthritis and spondyloarthritis but not in osteoarthritis (12). These authors further demonstrated the ability of soluble integrin ␤2 to inhibit monocytic cell adhesion to ICAM-1.…”

Sialic Acid Residues Are Essential for Cell Lysis Mediated by Leukotoxin from Aggregatibacter actinomycetemcomitans

“…Hybridoma cells producing monoclonal antibody KIM127, reacting with an epitope of human CD18 (43), were purchased from the American Type Culture Collection (Manassas, VA, USA), and the antibody was purified from culture supernatant as previously described (44). IgG1 from murine myeloma was used as an unspecific control antibody.…”

MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice

“…tissues, but also the shed molecules appear to act as dominantnegative inhibitors of CD11 or CD18 function on leukocytes (Gjelstrup et al, 2010).…”