Syndecan-1 regulates dendritic cell migration in cutaneous hypersensitivity to haptens.

In human dendritic cells (DCs), we previously demonstrated in vitro that syndecan-1 (SDC1) is downregulated during maturation correlating with enhanced motility. We investigated the effects of SDC1 on DC migration in vivo during TNCB(2,4,6-trinitro-1-chlorobenzene)-induced cutaneous hypersensitivity reaction (CHS) in mice. We show that DC in SDC1-deficient mice migrated faster and at a higher rate to lymph nodes draining the hapten-painted skin. Adoptive transfer of SDC1-deficient hapten- and fluorochrome-labelled DC into wild-type (WT) mice led to increased and faster migration of DC to paracortical lymph nodes, and to a stronger CHS compared to WT DC. In SDC1-/- mice, CCR7 remains longer on the DC surface within the first 15-minutes maturation (after LPS-induced maturation). In addition, a time-dependent upregulation of CCL2, CCL3, VCAM1 and talin was found during maturation in SDC1-/- DC. However, no difference in T-cell-stimulating capacity of SDC1-deficient DC was found compared to WT DC. Mechanistically, SDC1-deficient DC showed enhanced migration towards CCL21 and CCL19. This may result from functional overexpression of CCR7 in SDC1-/- DC. Increased and accelerated migration of otherwise functionally intact SDC1-deficient DC leads to an exacerbated CHS. Based on our results, we conclude that SDC1 on DC negatively regulates DC migration.

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.