Geometry sensing by dendritic cells dictates spatial organization and PGE(2)-induced dissolution of podosomes.
Assembly and disassembly of adhesion structures such as focal adhesions (FAs) and podosomes regulate cell adhesion and differentiation. On antigen-presenting dendritic cells (DCs), acquisition of a migratory and immunostimulatory phenotype depends on podosome dissolution by prostaglandin E(2) (PGE(2)). Whereas the effects of physico-chemical and topographical cues have been extensively studied on FAs, little is known about how podosomes respond to these signals. Here, we show that, unlike for FAs, podosome formation is not controlled by substrate physico-chemical properties. We demonstrate that cell adhesion is the only prerequisite for podosome formation and that substrate availability dictates podosome density. Interestingly, we show that DCs sense 3-dimensional (3-D) geometry by aligning podosomes along the edges of 3-D micropatterned surfaces. Finally, whereas on a 2-dimensional (2-D) surface PGE(2) causes a rapid increase in activated RhoA levels leading to fast podosome dissolution, 3-D geometric cues prevent PGE(2)-mediated RhoA activation resulting in impaired podosome dissolution even after prolonged stimulation. Our findings indicate that 2-D and 3-D geometric cues control the spatial organization of podosomes. More importantly, our studies demonstrate the importance of substrate dimensionality in regulating podosome dissolution and suggest that substrate dimensionality plays an important role in controlling DC activation, a key process in initiating immune responses.
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Koen
K
van den Dries
Suzanne F G
SF
van Helden
Joost
J
te Riet
Ruth
R
Diez-Ahedo
Carlo
C
Manzo
Machteld M
MM
Oud
Frank N
FN
van Leeuwen
Roland
R
Brock
Maria F
MF
Garcia-Parajo
Alessandra
A
Cambi
Carl G
CG
Figdor
D002448:Cell Adhesion; D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology*; D015232:Dinoprostone / Q000502:physiology*; D022001:Focal Adhesions; D006801:Humans; D013499:Surface Properties; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D020742:rhoA GTP-Binding Protein; D015232:Dinoprostone