Molecular Mechanisms Involved in Lymphocyte Recruitment in Inflamed Brain Microvessels: Critical Roles for P-Selectin Glycoprotein Ligand-1 and Heterotrimeric Gi-Linked Receptors

摘要: Lymphocyte recruitment into the brain is a critical event in pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. We developed novel intravital microscopy model to directly analyze through skull interactions between lymphocytes endothelium cerebral venules mice. No adhesive were observed nonactivated microcirculation. When activated by pretreating mice with TNF-α or LPS, proteolipid protein 139–151 autoreactive T rolled arrested; notably, only few peripheral lymph node cells firmly adhered. Abs anti-P-selectin glycoprotein ligand-1 anti-E- P-selectin blocked tethering rolling lymphocytes, suggesting that ligand-1/endothelial selectins are inflamed venules. E- expressed on vessels upon vivo activation had patchy distribution during preclinical phase active passive LFA-1/ICAM-1 α4 integrins/VCAM-1 supported rolling, but not relevant velocity. Firm arrest was mainly mediated LFA-1 ICAM-1. Pretreatment pertussis toxin integrin-dependent arrest, implicating requirement for Gi protein-dependent signaling from nonlymphoid districts. In conclusion, our data unveils molecular mechanisms controlling suggest new insights inflammatory diseases CNS.