Galectin-1 co-clusters CD43/CD45 on dendritic cells and induces cell activation and migration through Syk and protein kinase C signaling.
Galectin-1 is a galactoside-binding lectin expressed in multiple tissues that has pleiotropic immunomodulatory functions. We previously showed that galectin-1 activates human monocyte-derived dendritic cells (MDDCs) and triggers a specific genetic program that up-regulates DC migration through the extracellular matrix, an integral property of mucosal DCs. Here, we identify the galectin-1 receptors on MDDCs and immediate downstream effectors of galectin-1-induced MDDC activation and migration. Galectin-1 binding to surface CD43 and CD45 on MDDCs induced an unusual unipolar co-clustering of these receptors and activates a dose-dependent calcium flux that is abrogated by lactose. Using a kinome screen and a systems biology approach, we identified Syk and protein kinase C tyrosine kinases as mediators of the DC activation effects of galectin-1. Galectin-1, but not lipopolysaccharide, stimulated Syk phosphorylation and recruitment of phosphorylated Syk to the CD43 and CD45 co-cluster on MDDCs. Inhibitors of Syk and protein kinase C signaling abrogated galectin-1-induced DC activation as monitored by interleukin-6 production; and MMP-1, -10, and -12 gene up-regulation; and enhanced migration through the extracellular matrix. The latter two are specific features of galectin-1-activated DCs. Interestingly, we also found that galectin-1 can prime DCs to respond more quickly to low dose lipopolysaccharide stimulation. Finally, we underscore the biological relevance of galectin-1-enhanced DC migration by showing that intradermal injection of galectin-1 in MRL-fas mice, which have a defect in skin DC emigration, increased the in vivo migration of dermal DCs to draining lymph nodes.
Fulcher
Jennifer A
JA
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Chang
Margaret H
MH
Wang
Shuo
S
Almazan
Tim
T
Hashimi
Sara T
ST
Eriksson
Anna U
AU
Wen
Xiangshu
X
Pang
Mabel
M
Baum
Linda G
LG
Singh
Ram Raj
RR
Lee
Benhur
B
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D037483:Galectin 1 / Q000378:metabolism* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D051917:Leukosialin / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D053506:Matrix Metalloproteinase 10 / Q000235:genetics; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism
D037483:Galectin 1; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D051917:Leukosialin; D008070:Lipopolysaccharides; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D011493:Protein Kinase C; D017493:Leukocyte Common Antigens; D053506:Matrix Metalloproteinase 10; D053508:Matrix Metalloproteinase 12; D020781:Matrix Metalloproteinase 1; D002118:Calcium