TET inducible expression of the α4β7-integrin ligand MAdCAM-1 on the blood-brain barrier does not influence the immunopathogenesis of experimental autoimmune encephalomyelitis

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 MOG(aa35-55)-induced EAE.