Lysophosphatidylcholine-mediated functional inactivation of syndecan-4 results in decreased adhesion and motility of dendritic cells.
Following antigen contact, maturation and migration of DCs into lymphatic tissues are crucial to the developing immune response or maintenance of tolerance. Lysophosphatidylcholine (LysoPC) is generated during apoptosis of cells and acts as a "find-and-eat-me" signal thought to prevent autoimmunity. Moreover, LysoPC can activate PKCδ and initiates a signaling cascade that leads to phosphorylation and inactivation of syndecan-4 (SDC4), a heparansulfate proteoglycan integrin co-receptor. In human monocyte-derived DCs, we recently demonstrated that SDC4 is upregulated during maturation thereby stimulating DC motility. Here, we investigate the effects of LysoPC on DC motility as well as on the involvement of PKCδ phosphorylation-dependent regulation of DC motility by SDC4 and PKCα. Employing a static adhesion assay and videomicroscopy, we show that LysoPC inhibits adhesion of DCs to fibronectin and motility of DCs by decreasing podosome formation. Moreover, DC podosome formation and motility, which both are regulated by SDC4 and subject to control by PKCδ-dependent phosphorylation of SDC4, were inhibited in LysoPC-matured DCs. Thus, these DC are defective in adhesion and migration. Based on our results, we hypothesize that LysoPC released during apoptosis might delay DC migration to lymphoid organs and thus prevent autoimmunity.
Bühligen
Johannes
J
Department of Dermatology, Venerology and Allergology, Universitätsklinikum Leipzig, Leipzig, Germany.
Himmel
Mirko
M
Gebhardt
Carl
C
Simon
Jan C
JC
Ziegler
Wolfgang
W
Averbeck
Marco
M
D017209:Apoptosis; D015551:Autoimmunity; D051940:B7-2 Antigen / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D018715:Microscopy, Video; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D053671:Syndecan-4 / Q000378:metabolism*
D051940:B7-2 Antigen; C497964:CD86 protein, human; D005353:Fibronectins; D006684:HLA-DR Antigens; D047908:Intracellular Signaling Peptides and Proteins; D008244:Lysophosphatidylcholines; D008565:Membrane Proteins; C508304:SDC4 protein, human; D053671:Syndecan-4; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta