Enhanced Susceptibility to Endotoxic Shock and Impaired STAT3 Signaling in CD31-Deficient Mice

Abstract

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), an adhesion molecule expressed on hematopoietic and endothelial cells, mediates apoptosis, cell proliferation, and migration and maintains endothelial integrity in addition to its roles as a modulator of lymphocyte and platelet signaling and facilitator of neutrophil transmigration. Recent data suggest that CD31 functions as a scaffolding protein to regulate phosphorylation of the signal transducers and activators of transcription (STAT) family of signaling molecules, particularly STAT3 and STAT5. STAT3 regulates the acute phase response to innate immune stimuli such as lipopolysaccharide (LPS) and promotes recovery from LPS-induced septic shock. Here we demonstrate that CD31-deficient mice have reduced survival during endotoxic LPS-induced shock. As compared to wild-type controls, CD31-deficient mice showed enhanced vascular permeability; increased apoptotic cell death in liver, kidney, and spleen; and elevated levels of serum tumor necrosis factor ␣ (TNF-␣), interferon ␥ (IFN␥), MCP-1, MCP-5, sTNRF, and IL-6. In response to LPS in vivo and in vitro, splenocytes and endothelial cells from knockout mice had reduced levels of phosphorylated STAT3. These results suggest that CD31 is necessary for maintenance of endothelial integrity and prevention of apoptosis during septic shock and for STAT3-mediated acute phase responses that promote survival during septic shock. Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) belongs to the immunoglobulin family of cell adhesion molecules.

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.…”