Pharmacological targeting of ICAM-1 signaling in brain endothelial cells: potential for treating neuroinflammation.
(1) The vasculature of the blood-brain barrier allows only comparatively few leukocytes to enter and survey the healthy central nervous system (CNS). However, during pathological CNS inflammation, the number of leukocytes adhering to and penetrating the CNS vasculature increases strongly. (2) Endothelial adhesion molecules do not only mediate firm adhesion of leukocyte to vascular beds but also trigger signaling cascades within the endothelial cell, which play a crucial role in modulating subsequent leukocyte diapedesis. (3) Signaling through endothelial intercellular adhesion molecule-1 (ICAM-1, CD54) has been shown to induce changes of the endothelial cytoskeleton, transcription, and interendothelial junctions, all of which may be important in modulating endothelial disposition to infiltrating leukocytes. Furthermore, a number of recent reports document that drugs interfering with endothelial ICAM-1 signaling, efficiently reduce leukocyte migration both in vitro and in animal models of CNS inflammation. (4) These approaches are novel in as much as they target vascular beds rather than the penetrating leukocytes. Since endothelial ICAM-1 signaling appears to differ between different vascular beds we propose that such compounds could potentially be used as exquisite drugs in the treatment of neuroinflammatory diseases.
Turowski
Patric
P
Division of Cell Therapy, Institute of Ophthalmology, University College London, 11-43 Bath Street, London ECIV 9EL, UK. p.turowski@ucl.ac.uk
Adamson
Peter
P
Greenwood
John
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007962:Leukocytes / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D018799:Intercellular Adhesion Molecule-1