Article

Endothelial cell PECAM-1 confers protection against endotoxic shock

Medical College of Wisconsin, Milwaukee, Wisconsin, United States
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 02/2005; 288(1):H159-64. DOI: 10.1152/ajpheart.00500.2004
Source: PubMed

ABSTRACT

Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is a 130-kDa member of the Ig superfamily that is expressed on platelets and leukocytes and is highly enriched at endothelial cell-cell junctions. Previous studies showed that this vascular cell adhesion and signaling receptor functions to regulate platelet activation and thrombosis, to suppress apoptotic cell death, to mediate transendothelial migration of leukocytes, and to maintain the integrity of the vasculature. Because systemic exposure to the bacterial endotoxin LPS triggers an acute inflammatory response that involves many of these same processes, we compared the pathophysiological responses of wild-type versus PECAM-1-deficient mice to LPS challenge. We found that PECAM-1-deficient mice were significantly more sensitive to systemic LPS administration than their wild-type counterparts and that the lack of PECAM-1 expression at endothelial cell-cell junctions could account for the majority of the increased LPS-induced mortality observed. The diverse functional roles played by PECAM-1 in thrombosis, inflammation, apoptosis, and the immune response may make this molecule an attractive target for the development of novel therapeutics to manage and treat endotoxic shock.

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Available from: Carmen Bergom, Sep 17, 2014
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    • "CD31 is an important endothelial adhesion protein mediating endothelial integrity and other functions, including vascular permeability, regulation of bioavailability of nitric oxide (NO), and angiogenesis (Bagi et al. 2005; Carrithers et al. 2005; Liu et al. 2006; Maas et al. 2005; Wong et al. 2005). For instance, the CD31 knockout mice exhibit enhanced vascular permeability (Carrithers et al. 2005; Maas et al. 2005; Wong et al. 2005). VE-Cad also mediates vascular stability and angiogenesis (Carmeliet et al. 1999; Dejana and Giampietro 2012; Matheny et al. 2000; Vestweber 2008). "
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    • "CIA in DBA/1 mice Enhanced arthritis (Tada et al., 2003; Wong et al., 2005) Exposure to the bacterial endotoxin LPS Septic shock (Maas et al., 2005) Laser-induced and FeCl 3 endothelial injury Accelerated vascular occlusion (thrombosis) (Falati et al., 2006) Diet-induced non-alcoholic steatohepatitis Progressive liver disease (Goel et al., 2007) LDLR KO (hypercholesterolemic) mice Accelerated atherosclerosis (Goel et al., 2008) ApoE-deficient (hypercholesterolemic) mice Inhibited atherosclerosis (Harry et al., 2008) Bone marrow hematopoietic cell engraftment Hypersensitivity to macrophage CSF and receptor activator of NF-kB ligand; osteoclastic bone loss (Wu et al., 2009) Lipopolysaccharide (LPS)-induced endotoxemia Cytokine storm and acute respiratory distress syndrome due to accumulation of cytokine-producing leukocytes at sites of inflammation (Privratsky et al., 2010). "
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    ABSTRACT: Although it is expressed by all leukocytes, including T-, B-lymphocytes and dendritic cells, the immunoglobulin-like receptor CD31 is generally regarded by immunologists as a marker of endothelial cell lineage that lacks an established functional role in adaptive immunity. This perception has recently been challenged by studies that reveal a key role for this molecule in the regulation of T-cell homeostasis, effector function and trafficking. The complexity of the biological functions of CD31 results from the integration of its adhesive and signaling functions in both the immune and vascular systems. Signaling by means of CD31 is induced by homophilic engagement during the interactions of immune cells and is mediated by phosphatase recruitment or activation through immunoreceptor tyrosine inhibitory motifs (ITIMs) that are located in its cytoplasmic tail. Loss of CD31 function is associated with excessive immunoreactivity and susceptibility to cytotoxic killing. Here, we discuss recent findings that have brought to light a non-redundant, complex role for this molecule in the regulation of T-cell-mediated immune responses, with large impact on our understanding of immunity in health and disease.
    Full-text · Article · Jun 2013 · Journal of Cell Science
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    • "Alternatively, PECAM-1 could regulate leukocyte trafficking through modulation of vascular barrier function during leukocyte transendothelial migration. PECAM-1 has been demonstrated to play an important role in the regulation of vascular barrier function in vitro (Ferrero et al. 1995; Graesser et al. 2002; Biswas et al. 2006; Privratsky et al. 2011) and during LPSinduced endotoxemia and EAE in vivo (Graesser et al. 2002; Carrithers et al. 2005; Maas et al. 2005). In fact, decreased barrier function has previously been implicated in the observation that leukocytes accumulate to a higher degree in PECAM-1 −/− versus PECAM-1 +/+ mice subjected to EAE (Graesser et al. 2002), Consequently, although expression of PECAM-1 promotes leukocyte transendothelial migration (Muller et al. 1993; Vaporciyan et al. 1993; Wakelin et al. 1996), its role in maintaining vascular barrier function appears to dominate in certain inflammatory conditions. "
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