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

Medical College of Wisconsin, Milwaukee, Wisconsin, United States
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 01/2008; 293(6):G1205-14. DOI: 10.1152/ajpgi.00157.2007
Source: PubMed

ABSTRACT The severity of nonalcoholic steatohepatitis (NASH) is determined by environmental and genetic factors, the latter of which are incompletely characterized. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kDa transmembrane glycoprotein expressed on blood and vascular cells. In the present study, we provide data for the novel finding that genetic deficiency of PECAM-1 potentiates the development and progression of NASH. We found that the rate of development and severity of diet-induced NASH are markedly enhanced in PECAM-1-deficient [knockout (KO)] mice relative to wild-type (WT) mice, as measured by histological and biochemical evaluation. Livers from KO mice exhibited typical histological features of NASH, including macrovesicular fat accumulation, hepatocyte injury with infiltration of inflammatory cells, fibrosis, and heightened oxidative stress. Alanine aminotransferase, a marker for liver injury, was also significantly higher in KO compared with WT mice. Consistent with a role for PECAM-1 as a suppressor of proinflammatory cytokines, plasma levels of inflammatory cytokines, including TNF-alpha and monocyte chemoattractant protein-1 (MCP-1), were also significantly higher in KO compared with WT mice. These findings are the first to show that the PECAM-1-deficient mouse develops progressive nonalcoholic fatty liver disease (NAFLD), supporting a role for PECAM-1 as a negative regulator of NAFLD progression. Future examination of recently identified PECAM-1 allelic isoforms in humans as potential risk factors for developing NASH may be warranted.

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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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    Journal of Cell Science 06/2013; 126(11):2343-52. DOI:10.1242/jcs.124099 · 5.33 Impact Factor
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    • "Since PECAM-1 did not inhibit cellular cytokine synthesis (Figs. 2 and 3), we next examined whether PECAM-1 regulates cytokine levels through leukocyte trafficking and accumulation. Previous studies have demonstrated that mice expressing PECAM-1 have decreased accumulation of leukocytes at inflammatory sites during EAE (Graesser et al. 2002), collagen-induced arthritis (Tada et al. 2003), atherogenic diet-induced steatohepatitis (Goel et al. 2007), and LPS-induced endotoxemia (Maas et al. 2005), with the latter three studies also reporting that PECAM-1 lowered systemic levels of pro-inflammatory cytokines (Tada et al. 2003; Maas et al. 2005; Goel et al. 2007). In the current study, we found that the lungs of PECAM-1-deficient mice, compared to wild-type mice, contained significantly more leukocytes, mainly macrophages and neutrophils, with a concomitant increase in IL-6 levels following LPS-injection (Fig. 4). "
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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 · 2.30 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 · 2.30 Impact Factor
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