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


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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    • "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.
    Journal of Cell Science 06/2013; 126(11):2343-52. DOI:10.1242/jcs.124099 · 5.43 Impact Factor
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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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    ABSTRACT: To investigate the mechanism by which platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31), an immunoglobulin (Ig)-superfamily cell adhesion and signaling receptor, regulates pro-inflammatory cytokine levels. The purpose of the present investigation was to test the hypothesis that PECAM-1 influences circulating cytokine levels by regulating the trafficking of activated, cytokine-producing leukocytes to sites of inflammation. PECAM-1+/+ and PECAM-1-/- mice were subjected to lipopolysaccharide (LPS)-induced endotoxemia, and systemic cytokine levels were measured by Bioplex multiplex cytokine assays. Flow cytometry was employed to enumerate leukocytes at inflammatory sites and to measure cytokine synthesis in leukocyte sub-populations. Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokine levels in tissue samples and in supernatants of in vitro-stimulated leukocytes. We confirmed earlier reports that mice deficient in PECAM-1 had greater systemic levels of pro-inflammatory cytokines following intraperitoneal (IP) LPS administration. Interestingly, expression of PECAM-1, in mice, had negligible effects on the level of cytokine synthesis by leukocytes stimulated in vitro with LPS and in peritoneal macrophages isolated from LPS-injected mice. There was, however, excessive accumulation of macrophages and neutrophils in the lungs of PECAM-1-deficient, compared with wild-type, mice--an event that correlated with a prolonged increase in lung pro-inflammatory cytokine levels. Our results demonstrate that PECAM-1 normally functions to dampen systemic cytokine levels during LPS-induced endotoxemia by diminishing the accumulation of cytokine-producing leukocytes at sites of inflammation, rather than by modulating cytokine synthesis by leukocytes.
    Life sciences 11/2011; 90(5-6):177-84. DOI:10.1016/j.lfs.2011.11.002 · 2.70 Impact Factor
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    • "It is interesting to point out that virtually all of the studies thus far describing an antiinflammatory and protective effect of PECAM-1 (Table 2) have been performed in C57BL/6 mice, in which leukocyte transendothelial migration has been found to be largely PECAM-1-independent. These studies include evaluation of the effect of PECAM-1 deficiency on LPS-induced endotoxemia (Maas et al. 2005), EAE (Graesser et al. 2002), collagen-induced arthritis (Tada et al. 2003), and atherogenic diet-induced steatohepatitis (Goel et al. 2007), and atherosclerosis (Goel et al. 2008). It can be hypothesized that use of this particular strain of mice has enabled investigators to observe the anti-inflammatory effects of PECAM-1 without those effects being influenced by PECAM-1's proinflammatory promotion of leukocyte transmigration (Fig. 4a). "
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    ABSTRACT: Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a cell adhesion and signaling receptor that is expressed on hematopoietic and endothelial cells. PECAM-1 is vital to the regulation of inflammatory responses, as it has been shown to serve a variety of pro-inflammatory and anti-inflammatory functions. Pro-inflammatory functions of PECAM-1 include the facilitation of leukocyte transendothelial migration and the transduction of mechanical signals in endothelial cells emanating from fluid shear stress. Anti-inflammatory functions include the dampening of leukocyte activation, suppression of pro-inflammatory cytokine production, and the maintenance of vascular barrier integrity. Although PECAM-1 has been well-characterized and studied, the mechanisms through which PECAM-1 regulates these seemingly opposing functions, and how they influence each other, are still not completely understood. The purpose of this review, therefore, is to provide an overview of the pro- and anti-inflammatory functions of PECAM-1 with special attention paid to mechanistic insights that have thus far been revealed in the literature in hopes of gaining a clearer picture of how these opposing functions might be integrated in a temporal and spatial manner on the whole organism level. A better understanding of how inflammatory responses are regulated should enable the development of new therapeutics that can be used in the treatment of acute and chronic inflammatory disorders.
    Life sciences 07/2010; 87(3-4):69-82. DOI:10.1016/j.lfs.2010.06.001 · 2.70 Impact Factor
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