title: Schistosoma mansoni Soluble Egg Antigens Induce Expression of the Negative Regulators SOCS1 and SHP1 in Human Dendritic Cells via Interaction with the Mannose Receptor.
abstract: Schistosomiasis is a common debilitating human parasitic disease in (sub)tropical areas, however, schistosome infections can also protect against a variety of inflammatory diseases. This has raised broad interest in the mechanisms by which Schistosoma modulate the immune system into an anti-inflammatory and regulatory state. Human dendritic cells (DCs) show many phenotypic changes upon contact with Schistosoma mansoni soluble egg antigens (SEA). We here show that oxidation of SEA glycans, but not heat-denaturation, abrogates the capacity of SEA to suppress both LPS-induced cytokine secretion and DC proliferation, indicating an important role of SEA glycans in these processes. Remarkably, interaction of SEA glycans with DCs results in a strongly increased expression of Suppressor Of Cytokine Signalling1 (SOCS1) and SH2-containing protein tyrosine Phosphatase-1 (SHP1), important negative regulators of TLR4 signalling. In addition, SEA induces the secretion of transforming growth factor β (TGF-β), and the surface expression of the costimulatory molecules Programmed Death Ligand-1 (PD-L1) and OX40 ligand (OX40L), which are known phenotypic markers for the capacity of DCs to polarize naïve T cells into Th2/Treg cell subsets. Inhibition of mannose receptor (MR)-mediated internalization of SEA into DCs by blocking with allyl α-D-mannoside or anti-MR antibodies, significantly reduced SOCS1 and SHP1 expression. In conclusion, we demonstrate that SEA glycans are essential for induction of enhanced SOCS1 and SHP1 levels in DCs via the MR. Our data provide novel mechanistic evidence for the potential of S. mansoni SEA glycans to modulate human DCs, which may contribute to the capacity of SEA to down-regulate inflammatory responses.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Elsenoor J
authors.initials: EJ
authors.lastname: Klaver
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Loes M
authors.initials: LM
authors.lastname: Kuijk
authors.affiliation: Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel, Kiel, Germany.
authors.forename: Thisbe K
authors.initials: TK
authors.lastname: Lindhorst
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Irma
authors.initials: I
authors.lastname: van Die
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism* / Q000469:parasitology; D015870:Gene Expression; D006790:Host-Parasite Interactions; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D053278:OX40 Ligand / Q000235:genetics / Q000378:metabolism; D010063:Ovum / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000947:Antigens, Helminth; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D053278:OX40 Ligand; D011956:Receptors, Cell Surface; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C089251:TNFSF4 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6