Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors.
Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. We developed a novel intravital microscopy model to directly analyze through the skull the interactions between lymphocytes and the endothelium in cerebral venules of mice. No adhesive interactions were observed between lymphocytes and the nonactivated endothelium in the cerebral microcirculation. When brain venules were activated by pretreating mice with TNF-alpha or LPS, proteolipid protein 139-151 autoreactive T lymphocytes rolled and arrested; notably, only a few peripheral lymph node cells rolled and firmly adhered. Abs anti-P-selectin glycoprotein ligand-1 and anti-E- and P-selectin blocked tethering and rolling of autoreactive lymphocytes, suggesting that P-selectin glycoprotein ligand-1/endothelial selectins are critical in the recruitment of lymphocytes in inflamed brain venules. E- and P-selectin were expressed on cerebral vessels upon in vivo activation and had a patchy distribution during the preclinical phase of active and passive experimental autoimmune encephalomyelitis. LFA-1/ICAM-1 and alpha(4) integrins/VCAM-1 supported rolling, but were not relevant to rolling velocity. Firm arrest was mainly mediated by LFA-1 and ICAM-1. Pretreatment of autoreactive lymphocytes with pertussis toxin blocked integrin-dependent arrest, implicating a requirement for G(i) protein-dependent signaling in vessels from nonlymphoid districts. In conclusion, our data unveils the molecular mechanisms controlling the recruitment of autoreactive lymphocytes in inflamed cerebral vessels and suggest new insights into the pathogenesis of autoimmune inflammatory diseases of the CNS.
Piccio
Laura
L
Department of Pathology, University of Verona, Verona, Italy.
Rossi
Barbara
B
Scarpini
Elio
E
Laudanna
Carlo
C
Giagulli
Cinzia
C
Issekutz
Andrew C
AC
Vestweber
Dietmar
D
Butcher
Eugene C
EC
Constantin
Gabriela
G
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000502:physiology; D002465:Cell Movement; D002560:Cerebrovascular Circulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood* / Q000276:immunology* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006439:Hemodynamics; D016023:Integrins / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008833:Microcirculation; D008856:Microscopy, Fluorescence / Q000379:methods; D018448:Models, Immunological; D011956:Receptors, Cell Surface / Q000378:metabolism; D019087:Selectins / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D014699:Venules / Q000378:metabolism / Q000503:physiopathology
D001324:Autoantigens; D015815:Cell Adhesion Molecules; D016023:Integrins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011956:Receptors, Cell Surface; D019087:Selectins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go