The role of E‐ and P‐selectin in neutrophil and monocyte migration in adjuvant‐induced arthritis in the rat

Abstract

The role of the endothelial adhesion molecules E- and P-selectin in leukocyte accumulation in arthritis is not known. We investigated this role in rat adjuvant arthritis by employing adhesion function-blocking monoclonal antibodies (mAb) to rat P- and E-selectin. The acute migration (2 h) of radiolabeled rat blood neutrophils and monocytes to joints and skin was determined. Anti-P-selectin mAb significantly reduced accumulation of monocytes (by 50%) and neutrophils (by 40%) in the talar joint, and of neutrophils in tail joints (by 90%). Anti-E-selectin mAb alone did not attenuate leukocyte migration, but when combined with anti-P-selectin mAb, it enhanced inhibition of neutrophil accumulation in the talar and carpal joints. In the same animals, anti-P-selectin mAb significantly inhibited neutrophil and monocyte migration to dermal inflammatory reactions induced by zymosan-activated rat serum (ZAS) containing the chemotactic factor C5ades Arg, endotoxin (LPS), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). In contrast, anti-E-selectin mAb alone had no effect on monocyte or neutrophil accumulation in inflamed skin of arthritic animals, but again enhanced the inhibition when combined with mAb to P-selectin. The addition of anti-L-selectin mAb to anti-P- and E-selectin mAb did not further suppress monocyte or neutrophil migration to inflamed skin or joints. These results demonstrate that optimal leukocyte migration to arthritic joints and inflamed skin is P-selectin dependent, and E-selectin is not essential. However, E-selectin contributes to migration when P-selectin mechanisms are not operative. L-selectin does not play a role in E- and P-selectin-independent leukocyte migration to joints or skin inflammation in arthritic rats. However, it is likely that additional selectin-independent pathways also mediate neutrophil and monocyte migration to joint and skin inflammation.

Persistence of Pathogenic CD4+ Th1-Like Cells In Vivo in the Absence of IL-12 but in the Presence of Autoantigen

“…Moreover, Austrup et al showed that only Th1-like cells, but not Th2-like cells, can enter into cutaneous Th1-type inflammatory sites, presumably through E-and P-selectin-dependent mechanisms (32). These findings are further supported by evidence that the recruitment of pathogenic T cells into peripheral inflammatory sites, including adjuvant-induced arthritis, can be prevented using anti-E-and P-selectin mAbs (33,34). Additionally, activated T cells up-regulate their expression of E-and P-selectin ligand as observed in a sensitized skin model, and the presence of a combination of anti-E-and P-selectin Abs was able to block the migration of such T cells into the skin (29).…”

Blockade of Chemokine Receptor CXCR3 Inhibits T Cell Recruitment to Inflamed Joints and Decreases the Severity of Adjuvant Arthritis

“…synovial tissues (2, 3, 38, 39), and the presence of CC and CXC chemokines in synovial fluid (5,7,8,40). AA in the rat, used as a model for arthritic diseases in humans, has been useful to help understand the role of cell adhesion molecules in leukocyte migration in the pathogenesis of joint injury (9,11,12,16). In the present study, we examined the role of CXCR3 in the pathogenesis of AA.…”

“…Using this model, the role of several cell adhesion molecules, such as integrins and selectins, in leukocyte recruitment to inflamed joints has been extensively studied (9,(11)(12)(13)(14)(15)(16). A few studies were reported that examined the effect of blockade of chemokines or chemokine receptors in animal models of arthritis.…”

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

“…The hamster monoclonal antibody HRL-3 (gift of Dr D. C. Anderson, Pharmacia Upjohn, Kalamazoo, MI, USA and M. Miyasaka, Osaka, Japan) was used as an F(ab) 2 and it blocks the rat L-selectin function [17]. The effect of the monoclonal antibodies on PMNL migration in vivo was determined by giving animals an intravenous injection of the indicated monoclonal antibody, isotypematched control, or non-blocking control monoclonal antibodies, namely, HRL-4 F(ab) 2 anti-rat L-selectin, RP-2 anti-rat P-selectin, and 14G2 anti-E-selectin, as previously reported [18]. None of the monoclonal antibody treatments, in the form used, caused neutropenia or accelerated the clearance of the 111 In-labelled PMNLs from circulation, when compared with animals not receiving any antibodies.…”