Signal-regulatory protein alpha-CD47 interactions are required for the transmigration of monocytes across cerebral endothelium.
Monocyte infiltration into inflamed tissue requires their initial arrest onto the endothelial cells (ECs), followed by firm adhesion and subsequent transmigration. Although several pairs of adhesion molecules have been shown to play a role in the initial adhesion of monocytes to ECs, the mechanism of transendothelial migration is poorly defined. In this study, we have investigated the role of signal-regulatory protein (SIRP)alpha-CD47 interactions in monocyte transmigration across brain ECs. CD47 expression was observed in vivo on cerebral endothelium of both control animals and animals suffering from experimental allergic encephalomyelitis. To investigate whether SIRPalpha-CD47 interactions are instrumental in the trafficking of monocytes across cerebral EC monolayers, in vitro assays were conducted in which the migration of monocytes, but not adhesion, was found to be effectively diminished by blocking SIRPalpha and CD47 on monocytes and ECs, respectively. In this process, SIRPalpha was found to interact solely with its counterligand CD47 on ECs. Overexpression of the CD47 molecule on brain ECs significantly enhanced monocytic transmigration, but did not affect adhesion. SIRPalpha-CD47-mediated transendothelial migration involved Gi protein activity, a known signaling component of CD47. Finally, cross-linking of CD47 on brain ECs induced cytoskeletal reorganization of the endothelium, a process that was Gi protein independent. These data provide the first evidence that the interaction of CD47 with its monocytic counterligand SIRPalpha is of importance in the final step of monocyte trafficking into the brain, a critical event in the development of neuroinflammatory diseases.
de Vries
Helga E
HE
Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. HE.de_Vries.Cell@med.vu.nl
Hendriks
Jerome J A
JJ
Honing
Henk
H
De Lavalette
Chantal Renardel
CR
van der Pol
Susanne M A
SM
Hooijberg
Erik
E
Dijkstra
Christine D
CD
van den Berg
Timo K
TK
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000502:physiology*; D000943:Antigens, Differentiation; D001921:Brain / Q000098:blood supply / Q000473:pathology*; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D002448:Cell Adhesion; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules / Q000032:analysis / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D011971:Receptors, Immunologic
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D011971:Receptors, Immunologic; D019206:GTP-Binding Protein alpha Subunits, Gi-Go