Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1–deficient mice
Donnasue Graesser, Anna Solowiej, Monika Bruckner, Emily Osterweil, Amy Juedes, Sandra Davis, Nancy H. Ruddle, Britta Engelhardt, Joseph A. Madri
Donnasue Graesser, Anna Solowiej, Monika Bruckner, Emily Osterweil, Amy Juedes, Sandra Davis, Nancy H. Ruddle, Britta Engelhardt, Joseph A. Madri
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Article

Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1–deficient mice

Abstract

Platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31), a 130-kDa glycoprotein member of the Ig superfamily of transmembrane proteins, is expressed on endothelial cells, platelets, and subsets of leukocytes. It functions as a cell adhesion molecule as well as a scaffolding molecule capable of modulating cellular signaling pathways. In this study, using PECAM-1–deficient (KO) mice, as well as cells derived from these mice, we demonstrate that the absence of PECAM-1 expression is associated with an early onset of clinical symptoms during experimental autoimmune encephalomyelitis (EAE), a mouse model for the human autoimmune disease multiple sclerosis. During EAE, mononuclear cell extravasation and infiltration of the CNS occur at earlier time points in PECAM-KO mice than in wild-type mice. In vitro, T lymphocyte transendothelial migration across PECAM-KO endothelial cells is enhanced, regardless of expression of PECAM-1 on transmigrating T cells. Additionally, cultured PECAM-KO endothelial cells exhibit prolonged permeability changes in response to histamine treatment compared with PECAM-1–reconstituted endothelial cells. Lastly, we demonstrate an exaggerated and prolonged CNS vascular permeability during the development of EAE and a delay in restoration of dermal vascular integrity following histamine challenge in PECAM-KO mice.

Authors

Donnasue Graesser, Anna Solowiej, Monika Bruckner, Emily Osterweil, Amy Juedes, Sandra Davis, Nancy H. Ruddle, Britta Engelhardt, Joseph A. Madri

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Figure 4

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Immortalized endothelial cells derived from PECAM-KO mice support increa...
Immortalized endothelial cells derived from PECAM-KO mice support increased transmigration of MOG-specific T cells. (a and b) FACS analysis of immortalized endothelial cells derived from WT and KO brain (a) and KO lung and PECAM-reconstituted (RC) lung microvascular endothelial cells (b), illustrating the expression of VE-cadherin and ICAM-1 in all four cell types, but PECAM-1 expression only in the WT and PECAM-RC cells. (c and e) In vitro adhesion assays illustrating no differences in MOG-specific T cell adhesion to WT, PECAM-KO, and PECAM-RC endothelioma cells. (d and f) In vitro transmigration assays similar to those in Figure 2c were performed using MOG-specific T cells transmigrating across monolayers of endothelioma cell lines. Transmigration of T cells across KO endotheliomas derived from brain and lung was consistently and significantly increased in comparison with transmigration across WT and PECAM-RC endotheliomas. In c and d WT T lymphocytes were used, and in e and f KO T lymphocytes were used. n = 4.