Endothelial cell PECAM-1 confers protection against endotoxic shock

Abstract

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.

CD31 signals confer immune privilege to the vascular endothelium

“…and endotoxemia (18,19), suggesting that CD31 signals play a protective role under conditions of immunological stress.…”

“…In contrast, despite the large body of evidence pointing to an endothelial-specific antiapoptotic pathway operational during immune-mediated cell death (18,19), a potential role for CD31 in protecting ECs from inflammatory insults inducing the extrinsic pathway of apoptosis has not been investigated.…”

Different susceptibilities of PECAM-deficient mouse strains to spontaneous idiopathic pneumonitis

“…Further, when mice genetically deficient for PECAM were first derived in the C57BL/6 strain, they were able to use PECAM-independent mechanisms to mobilize normal numbers of monocytes and neutrophils in several models of inflammation (Duncan et al, 1999). While these PECAM-deficient mice were subsequently found to have some deficiencies in their inflammatory responses in certain models (Carrithers et al, 2005;Graesser et al, 2002;Maas et al, 2005;Solowiej et al, 2003;Thompson et al, 2001), C57BL/6 mice appear to be unique in their relative insensitivity to PECAM blockade. All other mouse strains tested have significantly reduced inflammatory reactions when PECAM is genetically deficient or blocked in wild-type mice using antibodies.…”

Targeting PECAM-1 for anti-cancer therapy

“…[7][8][9] With respect to its potential activity in the pathogenesis of tumors, this cell adhesion and signaling molecule has been implicated in angiogenesis, 10-13 vascular permeability, 14 leukocyte (neutrophils and monocytes) recruitment out of the circulation [15][16][17] and endothelial resistance to endotoxic stress 18,19 and apoptotic insults. 20 Consequently, by inhibiting tumor neovascularization, altering vascular permeability, increasing endothelial susceptibility to apoptotic stress and limiting leukocyte infiltration within the tumor, antagonism of PECAM-1 could inhibit tumor growth independent of any direct effects on the tumor.…”

“…However, given its potential role as a mediator of leukocyte diapedesis 16,17 and in protecting against apoptotic and endotoxic stresses, [18][19][20] only human clinical trials will be able to establish the ultimate safety of anti-PECAM-1 therapy.…”