The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis
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.
- SourceAvailable from: Gloria L Fawcett
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- "Platelet/endothelial cell adhesion molecule 1 (Pecam1) is a glycoprotein located near a QTL for fatty liver  and diabetes . Previous work has suggested that Pecam1 is involved in regulating inflammation and higher expression of this gene protects the liver from the effect of high dietary fat and NAFLD . High-fat fed SM/J displayed significantly higher Pecam1 expression levels when compared to low-fat fed individuals. "
ABSTRACT: The liver plays a major role in regulating metabolic homeostasis and is vital for nutrient metabolism. Identifying the genetic factors regulating these processes could lead to a greater understanding of how liver function responds to a high-fat diet and how that response may influence susceptibilities to obesity and metabolic syndrome. In this study we examine differences in hepatic gene expression between the LG/J and SM/J inbred mouse strains and how gene expression in these strains is affected by high-fat diet. LG/J and SM/J are known to differ in their responses to a high-fat diet for a variety of obesity- and diabetes-related traits, with the SM/J strain exhibiting a stronger phenotypic response to diet. Dietary intake had a significant effect on gene expression in both inbred lines. Genes up-regulated by a high-fat diet were involved in biological processes such as lipid and carbohydrate metabolism; protein and amino acid metabolic processes were down regulated on a high-fat diet. A total of 259 unique transcripts exhibited a significant diet-by-strain interaction. These genes tended to be associated with immune function. In addition, genes involved in biochemical processes related to non-alcoholic fatty liver disease (NAFLD) manifested different responses to diet between the two strains. For most of these genes, SM/J had a stronger response to the high-fat diet than LG/J. These data show that dietary fat impacts gene expression levels in SM/J relative to LG/J, with SM/J exhibiting a stronger response. This supports previous data showing that SM/J has a stronger phenotypic response to high-fat diet. Based upon these findings, we suggest that SM/J and its cross with the LG/J strain provide a good model for examining non-alcoholic fatty liver disease and its role in metabolic syndrome.BMC Genomics 02/2014; 15(1):99. DOI:10.1186/1471-2164-15-99 · 3.99 Impact Factor
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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). "
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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- "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). "
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