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

Goel, Reema; Boylan, Brian; Gruman, Lynn M.; Newman, Peter J.; North, Paula E.; Newman, Debra K.

doi:10.1152/ajpgi.00157.2007

Cited by 41 publications

(43 citation statements)

References 67 publications

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“…PECAM-1 promotes inflammation by facilitating leukocyte transendothelial migration (Muller et al, 1993;Vaporciyan et al, 1993;Wakelin et al, 1996) and by serving as a mechanosensor for fluid shear stress (Tzima et al, 2005), but dampens inflammation via its ability to: (1) inhibit cellular activation (Falati et al, 2006;Newman et al, 2001;Newton-Nash and Newman, 1999;Patil et al, 2001;Rui et al, 2007;Wilkinson et al, 2002;Wong et al, 2002); (2) reduce proinflammatory cytokine levels (Carrithers et al, 2005;Goel et al, 2007;Maas et al, 2005;Tada et al, 2003); (3) decrease leukocyte accumulation at sites of inflammation (Carrithers et al, 2005;Goel et al, 2007;Goel et al, 2008;Maas et al, 2005;Tada et al, 2003); and (4) maintain and restore vascular integrity (Biswas et al, 2006;Carrithers et al, 2005;Ferrero et al, 1995;Graesser et al, 2002;Maas et al, 2005). Consequently, elucidating the mechanisms by which PECAM-1 mediates both its pro-and anti-inflammatory effects has the potential to improve our understanding of how cells and tissues integrate these seemingly opposing biological signals.…”

Section: Discussionmentioning

confidence: 99%

Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity

Privratsky

Paddock

Florey

et al. 2011

Journal of Cell Science

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SummaryPECAM-1 (CD31) is a cellular adhesion and signaling receptor that is highly expressed at endothelial cell-cell junctions in confluent vascular beds. Previous studies have implicated PECAM-1 in the maintenance of vascular barrier integrity; however, the mechanisms behind PECAM-1-mediated barrier protection are still poorly understood. The goal of the present study, therefore, was to examine the pertinent biological properties of PECAM-1 (i.e. adhesion and/or signaling) that allow it to support barrier integrity. We found that, compared with PECAM-1-deficient endothelial cells, PECAM-1-expressing endothelial cell monolayers exhibit increased steady-state barrier function, as well as more rapid restoration of barrier integrity following thrombin-induced perturbation of the endothelial cell monolayer. The majority of PECAM-1-mediated barrier protection was found to be due to the ability of PECAM-1 to interact homophilically and become localized to cell-cell junctions, because a homophilic binding-crippled mutant form of PECAM-1 was unable to support efficient barrier function when re-expressed in cells. By contrast, cells expressing PECAM-1 variants lacking residues known to be involved in PECAM-1-mediated signal transduction exhibited normal to near-normal barrier integrity. Taken together, these studies suggest that PECAM-1-PECAM-1 homophilic interactions are more important than its signaling function for maintaining the integrity of endothelial cell junctions.

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Section: Discussionmentioning

confidence: 99%

Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity

Privratsky

Paddock

Florey

et al. 2011

Journal of Cell Science

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“…Therefore, it is possible to use a homophilic peptide or an appropriate peptidomimetic compound to mimic the cis-homo-oligomerization step and rescue the lost physiologic immunoregulatory function of CD31 on activated T cells. Such a therapeutic approach might be useful for treating debilitating chronic immunoinflammatory diseases in which CD31 signaling is suspected to play an important protective role, such as in rheumatoid arthritis (9), multiple sclerosis (8), inflammatory liver disease (40), and atherothrombosis (24,27,41).…”

Section: Discussionmentioning

confidence: 99%

TCR Stimulation Drives Cleavage and Shedding of the ITIM Receptor CD31

Fornasa

Groyer

Clément

et al. 2010

The Journal of Immunology

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CD31 is a transmembrane molecule endowed with T cell regulatory functions owing to the presence of 2 immunotyrosine-based inhibitory motifs. For reasons not understood, CD31 is lost by a portion of circulating T lymphocytes, which appear prone to uncontrolled activation. In this study, we show that extracellular T cell CD31 comprising Ig-like domains 1 to 5 is cleaved and shed from the surface of human T cells upon activation via their TCR. The shed CD31 can be specifically detected as a soluble, truncated protein in human plasma. CD31 shedding results in the loss of its inhibitory function because the necessary cis-homo–oligomerization of the molecule, triggered by the trans-homophilic engagement of the distal Ig-like domain 1, cannot be established by CD31shed cells. However, we show that a juxta-membrane extracellular sequence, comprising part of the domain 6, remains expressed at the surface of CD31shed T cells. We also show that the immunosuppressive CD31 peptide aa 551–574 is highly homophilic and possibly acts by homo-oligomerizing with the truncated CD31 remaining after its cleavage and shedding. This peptide is able to sustain phosphorylation of the CD31 ITIM686 and of SHP2 and to inhibit TCR-induced T cell activation. Finally, systemic administration of the peptide in BALB/c mice efficiently suppresses Ag-induced T cell-mediated immune responses in vivo. We conclude that the loss of T cell regulation caused by CD31 shedding driven by TCR stimulation can be rescued by molecular tools able to engage the truncated juxta-membrane extracellular molecule that remains exposed at the surface of CD31shed cells.

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“…In experimental therapeutic settings, for example to prevent transplant rejection, the delivery of antigen by selective routes, such as oral or nasal administration, can induce tolerance to the graft (Ma et al, 2010). (Graesser et al, 2002) 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).…”

Section: Box 1 Key Events In the Immune Responsementioning

confidence: 99%

An immunologist's guide to CD31 function in T-cells

Marelli‐Berg

Clément

Mauro

et al. 2013

Journal of Cell Science

118

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SummaryAlthough 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.

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

Abstract: DK. The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis.

Cited by 41 publications

References 67 publications

Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity

Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity

TCR Stimulation Drives Cleavage and Shedding of the ITIM Receptor CD31

An immunologist's guide to CD31 function in T-cells

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