Adhesion molecules mediating neutrophil migration to arthritis in vivo and across endothelium and connective tissue barriers in vitro

Abstract

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.

Lymphocyte Function-Associated Antigen-1 Blockade by Statins: Molecular Basis and Biological Relevance

“…Animal experiments using anti-LFA-1 monoclonal antibodies (mAbs) indicate that the LFA-1/ICAM interaction is involved in the pathogenesis of allergic contact dermatitis (Scheynius et al 1996), arthritis (Issekutz 1998), transplant rejection (Poston et al 2000), and ischemia/reperfusion injury (Martin et al 2000). Indeed, treatment with a blocking anti-LFA-1 mAb led to significant clinical effects in psoriasis patients (Gottlieb et al 2002).…”

“…The LFA-1/ICAM-1 interaction is known to play a pivotal role in leukocyte recruitment, and in similar animal models, anti-LFA-1 mAbs have been shown to be efficacious (e.g., Mulligan et al 1998;Issekutz 1998;Russel et al 1995). Thus, it is possible that LFA-1 inhibition by statins may contribute to the overall protective effect observed in these models.…”

Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

“…For example, VLA-4 may act as a costimulatory molecule on T cells and could therefore influence T-cell activation and differentiation (11)(12)(13)(14). Furthermore, VLA-4 may have a role in collagen matrix reorganization in response to injury or inflammation (15), memory B-cell activation (16), and eosinophil and neutrophil migration into inflamed tissue (17,18). In addition, VLA-4 interactions with either VCAM-1 or fibronectin have been shown to protect cells from apoptosis, possibly due to the upregulation of Bcl-2, an anti-apoptotic regulatory protein (19)(20)(21).…”

Towards an in vitro model for acute hemorrhagic conjunctivitis: cytokine-mediated vascular endothelial cell activation triggered by enterovirus type 70 infection

“…Human umbilical vein endothelial cells (HUVECs) were isolated and cultured in gelatin-coated flasks as described by Jaffe et al (1973), with modifications reported previously (Issekutz, 1998). Human corneal epithelial cells (HCEs), kindly provided as an immortalized cell line by Dr. M. Griffith, University of Ottawa (Griffith et al, 1999), were cultured as monolayers in M199 medium supplemented with 10% heat-inactivated fetal calf serum (FCS) and 1% insulin-transferrin-selenium (ITS; Gibco-BRL, Mississauga ON, Canada).…”