JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling.
The membrane-associated adhesion molecule JAM-A is required for neutrophil infiltration in inflammatory or ischemic tissues. JAM-A expressed in both endothelial cells and neutrophils has such a role, but the mechanism of action remains elusive. Here we show that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro, which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A concentrates in a polarized fashion at the leading edge and uropod. Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin beta1. Clustering of beta1 integrin leads to JAM-A co-clustering, whereas clustering of JAM-A does not induce integrin association. Neutrophils derived from JAM-A-null mice are unable to correctly internalize beta1 integrins upon chemotactic stimuli and this causes impaired uropod retraction and cell motility. Consistently, inhibition of integrin internalization upon treatment with BAPTA-AM induces a comparable phenotype. These data indicate that JAM-A is required for the correct internalization and recycling of integrins during cell migration and might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired.
Cera
Maria Rosaria
MR
FIRC Institute of Molecular Oncology, Milan, Italy.
Fabbri
Monica
M
Molendini
Cinzia
C
Corada
Monica
M
Orsenigo
Fabrizio
F
Rehberg
Markus
M
Reichel
Christoph A
CA
Krombach
Fritz
F
Pardi
Ruggero
R
Dejana
Elisabetta
E
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D022162:Cytoplasmic Vesicles / Q000502:physiology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism*; D007975:Leukotriene B4 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D002614:Chelating Agents; C407243:F11R protein, human; C498686:F11r protein, mouse; D007136:Immunoglobulins; D019012:Integrin beta1; D009842:Oligopeptides; D011956:Receptors, Cell Surface; C113617:Trp-Lys-Tyr-Met-Val-Met; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D007975:Leukotriene B4; D004533:Egtazic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D020827:rap1 GTP-Binding Proteins