Leukocyte transmigration requires kinesin-mediated microtubule-dependent membrane trafficking from the lateral border recycling compartment.
Diapedesis of leukocytes across endothelial cells is a crucial step in both the innate and adaptive immune responses. Surface molecules on leukocytes and endothelial cells critical for diapedesis have been identified, but the mechanisms underlying this process are not understood. Homophilic interaction between platelet/endothelial cell adhesion molecule (PECAM) on leukocytes and PECAM at the endothelial border triggers targeted recycling of membrane from a reticulum localized close to the endothelial cell lateral border. This membrane surrounds the transmigrating leukocyte (Mamdouh, Z., X. Chen, L.M. Pierini, F.R. Maxfield, and W.A. Muller. 2003. Nature. 421:748-753). How this process occurs and whether it is required for diapedesis independent of PECAM are not known. We now report that targeted recycling from this lateral border recycling compartment (LBRC) is required for diapedesis, is mediated by kinesin family molecular motors, and requires normally functioning endothelial microtubules. Selective disruption of microtubules or inhibition of kinesin motor domain blocked targeted recycling and diapedesis of monocytes. Furthermore, targeted recycling of membrane from the LBRC was required for transmigration of lymphocytes, which migrate independently of PECAM. Thus, trafficking of membrane from the LBRC to surround leukocytes may be a general requirement for migration of leukocytes across the endothelial cell border. Furthermore, these data provide the first demonstration of a role for endothelial microtubules and kinesins in promoting diapedesis, and a mechanism to explain targeted recycling.
Mamdouh
Zahra
Z
Department of Pathology and Laboratory Medicine and the Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10021, USA.
Kreitzer
Geri E
GE
Muller
William A
WA
D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002451:Cell Compartmentation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003703:Demecolcine / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007365:Intercellular Junctions / Q000187:drug effects; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D020409:Molecular Motor Proteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003703:Demecolcine; D018799:Intercellular Adhesion Molecule-1; D016547:Kinesins; D020409:Molecular Motor Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099152:Cadherin 5