Beta1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity.
Inhibiting the alpha(4) subunit of the integrin heterodimers alpha(4)beta(1) and alpha(4)beta(7) with the monoclonal antibody natalizumab is an effective treatment for multiple sclerosis (MS). However, the pharmacological action of natalizumab is not understood conclusively. Previous studies suggested that natalizumab inhibits activation, proliferation, or extravasation of inflammatory cells. To specify which mechanisms, cell types, and alpha(4) heterodimers are affected by the antibody treatment, we studied MS-like experimental autoimmune encephalomyelitis (EAE) in mice lacking the beta(1)-integrin gene either in all hematopoietic cells or selectively in T lymphocytes. Our results show that T cells critically rely on beta(1) integrins to accumulate in the central nervous system (CNS) during EAE, whereas CNS infiltration of beta(1)-deficient myeloid cells remains unaffected, suggesting that T cells are the main target of anti-alpha(4)-antibody blockade. We demonstrate that beta(1)-integrin expression on encephalitogenic T cells is critical for EAE development, and we therefore exclude alpha(4)beta(7) as a target integrin of the antibody treatment. T cells lacking beta(1) integrin are unable to firmly adhere to CNS endothelium in vivo, whereas their priming and expansion remain unaffected. Collectively, these results suggest that the primary action of natalizumab is interference with T cell extravasation via inhibition of alpha(4)beta(1) integrins.
Bauer
Martina
M
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Brakebusch
Cord
C
Coisne
Caroline
C
Sixt
Michael
M
Wekerle
Hartmut
H
Engelhardt
Britta
B
Fässler
Reinhard
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D015551:Autoimmunity / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects; D002464:Cell Migration Inhibition; D002490:Central Nervous System / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental; D004727:Endothelium; D007249:Inflammation / Q000473:pathology*; D039441:Integrin alpha4; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000276:immunology*; D051379:Mice; D000069442:Natalizumab; D013601:T-Lymphocytes / Q000502:physiology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D000069442:Natalizumab; D039441:Integrin alpha4