Acceleration of the onset of collagen‐induced arthritis by a deficiency of platelet endothelial cell adhesion molecule 1

Abstract

Objective. Platelet endothelial cell adhesion molecule 1 (PECAM-1; CD31) is a member of the immunoglobulin superfamily that is expressed in platelets, leukocytes, and endothelial cells. PECAM-1 has been shown to play a role in transendothelial migration of leukocytes and contains immunoreceptor tyrosinebased inhibitory motifs in its cytoplasmic tail and inhibits cellular responses. We examined the role of PECAM-1 in the development of collagen-induced arthritis (CIA).Methods. CIA was induced in PECAM-1-deficient DBA/1 mice. The incidence of arthritis and the arthritis index were examined. Anti-type II collagen (anti-CII) antibody levels and interferon-␥ (IFN␥) production by lymph node cells and spleen cells were determined. Lymphocytes from arthritic PECAM-1-deficient and wild-type mice were labeled with dye, transferred to arthritic PECAM-1 ؉/؊ mice, and cell migration to inflamed joints was examined.Results. PECAM-1-deficient mice showed accelerated onset of arthritis and increased severity only during the early phase. Anti-CII antibody levels were also increased during the early phase. IFN␥ production by lymph node cells and spleen cells from PECAM-1-deficient mice in response to CII was higher than that in wild-type mice. Lymphocytes from arthritic PECAM-1-deficient mice showed accelerated migration to inflamed joints, but not lymph nodes or spleen. The development of anti-CII antibody-induced arthritis was similar in PECAM-1-deficient and wild-type mice.Conclusion. These results indicate that PECAM-1 negatively regulates humoral and cell-mediated immune responses and lymphocyte migration into joints and, consequently, the development of CIA. In addition, the role of PECAM-1 in the transendothelial migration of leukocytes appears to be redundant in this model.

The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis

“…Nevertheless, we demonstrate in the present study that macrophages readily home into the inflamed livers of PECAM-1-deficient mice fed an atherogenic diet, which indicates that PECAM-1 homophilic interactions are not required for macrophage recruitment into the liver under these conditions. Our observation is consistent with the previous finding that PECAM-1 does not play a major role in transmigration of neutrophils into the liver during endotoxemia (13) and with the finding, in at least four different in vivo models of inflammation, that the blood vessels of PECAM-1-deficient mice are particularly susceptible to vascular leakage (9,29,41,63,71). Together, these results suggest either that PECAM-1 homophilic interactions are not as important for leukocyte transmigration into the liver as they are in other tissues or that increased vascular permeability in PECAM-1-deficient vessels overcomes the need for PECAM-1 homophilic interactions in transmigration of inflammatory cells into damaged tissue.…”

“…Second, several recent studies have provided evidence that PECAM-1 suppresses production of proinflammatory cytokines. Specifically, plasma concentrations of IL-1, TNF-␣, MCP-1, IFN-␥, and IL-6 were all found to be significantly increased 24 h following injection of lipopolysaccharide into PECAM-1-deficient relative to WT mice (9, 41), whereas IFN-␥ production by PECAM-1-deficient T cells was found to be four times that of WT T cells in mice in which collagen-induced arthritis had been experimentally induced (63). Although little is known about the mechanism by which PECAM-1 normally suppresses ROS production, Cepinskas et al (10) have provided evidence that the mechanism by which PECAM-1 suppresses production of proinflammatory cytokines may involve interference with translocation of nuclear factor (NF)-B into the nucleus of inflamed endothelial cells.…”

“…PECAM-1 has been shown in a number of experimental systems to function as an inhibitory receptor that limits agonist-induced activation of blood and vascular cells (47). To date, PECAM-1 engagement or expression has been shown to inhibit T cell (49), B cell (70), mast cell (72), and platelet (25,52,57) reactivity and to inhibit production of proinflammatory cytokines in vivo (9,41,63). PECAM-1 has also been implicated in maintaining vascular integrity in at least four different in vivo models of inflammation, including intradermal injection of histamine (29), autoimmune encephalomyelitis (29), collagen-induced arthritis (63,71), and lipopolysaccharide-induced endotoxemia (9,41).…”

Short-term sPECAM-Fc treatment ameliorates EAE while chronic use hastens onset of symptoms

“…This effect was attributed to increased vascular permeability, particularly of the blood-brain barrier, in the PECAM-1 deficient mice. Similar results were seen in studies of PECAM-1 deficient mice in collagen induced arthritis models (Tada et al, 2003;Wong et al, 2005). Both of these studies were carried out in the C57Bl/6 strain of mice, which are unique in that they do not respond to PECAM blockade in several inflammatory models (Schenkel et al, 2004).…”

CD31 signals confer immune privilege to the vascular endothelium

“…However, these animals display exaggerated disease severity in inducible experimental models of T-cell-mediated inflammation, including experimental autoimmune encephalomyelitis (15), collagen-induced arthritis (16), atherosclerosis (17),…”