TET inducible expression of the [alpha]4[beta]7-integrin ligand MAdCAM-1 on the blood-brain barrier does not influence the immunopathogenesis of experimental autoimmune encephalomyelitis

• Published in: European journal of immunology Vol. 41; no. 3; pp. 813 - 821
• Main Authors: Doring, Axinia, Pfeiffer, Friederike, Meier, Matthias, Dehouck, Bénédicte, Tauber, Silke, Deutsch, Urban, Engelhardt, Britta
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 01.03.2011
• Subjects: Beta; Blood-brain barrier; Cell adhesion & migration; Ligands; Pathogenesis
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201040912

Inhibiting the [alpha]4 subunit of the integrin heterodimers [alpha]4[beta]1 and [alpha]4[beta]7 with the mab natalizumab is an effective treatment of multiple sclerosis (MS). Which of the two [alpha]4 heterodimers is involved in disease pathogenesis has, however, remained controversial. Whereas the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, is ameliorated in [beta]7-integrin-deficient C57BL/6 mice, neutralizing antibodies against the [beta]7-integrin subunit or the [alpha]4[beta]7-integrin heterodimer fail to interfere with EAE pathogenesis in the SJL mouse. To facilitate [alpha]4[beta]7-integrin-mediated immune-cell trafficking across the blood-brain barrier (BBB), we established transgenic C57BL/6 mice with endothelial cell-specific, inducible expression of the [alpha]4[beta]7-integrin ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 using the tetracycline (TET)-OFF system. Although TET-regulated MAdCAM-1 induced [alpha]4[beta]7-integrin mediated interaction of [alpha]4[beta]7+/[alpha]4[beta]1- T cells with the BBB in vitro and in vivo, it failed to influence EAE pathogenesis in C57BL/6 mice. TET-regulated MAdCAM-1 on the BBB neither changed the localization of central nervous system (CNS) perivascular inflammatory cuffs nor did it enhance the percentage of [alpha]4[beta]7-integrin+ inflammatory cells within the CNS during EAE. In conclusion, our study demonstrates that ectopic expression of MAdCAM-1 at the BBB does not increase [alpha]4[beta]7-integrin-mediated immune cell trafficking into the CNS during MOGaa35-55-induced EAE. [PUBLICATION ABSTRACT]