PECAM-1: conflicts of interest in inflammation

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.

Figure 1. The structure and function of PECAM-1

PECAM-1 is a 130 kDa type I transmembrane glycoprotein belonging to the Ig-like superfamily of adhesion molecules. The biological functions of PECAM-1 have been mapped to specific regions of the PECAM-1 molecule as shown in the figure. Residues important for mediating homophilic and heterophilic binding interactions are located within Ig-domain 1 and Ig-domains 5 & 6, respectively. Localization of PECAM-1 to membrane microdomains occurs after palmitoylation of residue Cys₅₉₅. Two ITIMs encompass residues Y₆₆₃ and Y686 within the cytoplasmic tail and are able to serve as docking sites for cytosolic signaling molecules when the tyrosines become phosphorylated.

Figure 2. The pro-inflammatory functions of PECAM-1

PECAM-1 serves a variety of pro-inflammatory functions in both leukocytes and endothelial cells. 1. Upstream of the leukocyte adhesion cascade, PECAM-1 promotes chemokine-directed migration of leukocytes by enhancing actin polymerization and cycling. 2. The binding interaction between CD177 on neutrophils and PECAM-1 on endothelial cells is the only known heterotypic binding interaction that has been shown to be important for PECAM-1-mediated leukocyte transmigration. 3. Homotypic binding interactions between PECAM-1 on leukocytes and endothelial cells are thought to be essential for leukocyte diapedesis as blocking these interactions prevents diapedesis. 4. Downstream of homotypic binding interactions, PECAM-1 is able to activate integrins on leukocytes that are essential for adhesion to endothelial cells and passage through the basement membrane. Postulated mechanisms of PECAM-1-mediated integrin activation on leukocytes include, but are not limited to, the activation of PI3K and the GTPase Rap1. 5. During both paracellular (shown in figure) and transcellular (not shown) leukocyte transmigration, PECAM-1 is part of a surface connected membrane compartment termed the LBRC that likely serves to provide more surface area and/or unligated PECAM and other molecules to the leukocyte. 6. PECAM-1 also is able to transmit mechanical signals in endothelial cells in response to fluid forces. PECAM-1 becomes activated, and through poorly understood mechanisms, is able to transduce signals to VE-cadherin, which then activates VEGFR2. This results in the activation of integrins and the pro-inflammatory transcription factor NF-κB, which promotes atherosclerotic lesion development.

Figure 3. PECAM-1/SHP-2 interactions dampen leukocyte activation

The PECAM-1 cytoplasmic tail contains ITIM tyrosines, which when phosphorylated, can serve as docking sites for cytosolic signaling molecules. Most times, ITIMs recruit phosphatases to counteract kinases that become activated by ITAMs. The best characterized phosphatase that is recruited by PECAM-1 is SHP-2. PECAM-1/SHP-2 interactions have been proposed to inhibit activation of B cell, T cell, mast cell, and macrophage functions as represented in the figure.

Figure 4. Proposed schematic for the interplay of the pro- and anti-inflammatory properties of PECAM-1 in different genetic strains of mice

(a) PECAM-1 is known to possess both pro- and anti-inflammatory properties as displayed in the figure, which would be proposed to largely offset each other during inflammation. (b) Most studies to date, however, have used the C57BL/6 genetic strain of mice and have described a predominant anti-inflammatory effect of PECAM-1 in models of inflammation. Loss of PECAM-1 in most strains of mice results in profound defects in leukocyte transmigration, however, this is not true in C57BL/6 mice, where PECAM-1 plays only a minor role in this process. As a result, the ability of PECAM-1 to suppress cytokine production and/or maintain vascular integrity in response to inflammatory insult tends to dominate in C57BL/6 mice, lessening their severity of their disease. It is hypothesized, therefore, that examining inflammatory disease models in other strains of mice, where the pro- and anti-inflammatory functions of PECAM-1 should largely offset each other, will not show predominate anti-inflammatory effects of PECAM-1.