Schistosoma mansoni Soluble Egg Antigens Induce Expression of the Negative Regulators SOCS1 and SHP1 in Human Dendritic Cells via Interaction with the Mannose Receptor.

Irma van Die,Geoffrey N. Gobert,Elsenoor J. Klaver,Thisbe K. Lindhorst,Richard D. Cummings,Loes M. Kuijk

doi:10.1371/journal.pone.0124089

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.

Highlights

Parasitic helminths have evolved to suppress inflammatory responses of the immune system to survive in their hosts [1]
PI treatment caused loss of binding by the recombinant C-type lectin receptors (CLRs)-Fc hybrids macrophage galactose-type lectin (MGL)-Fc, dendritic cells (DCs)-SIGN-Fc and mannose receptor (MR)-Fc to soluble egg antigens (SEA) (Fig 1A), indicating that the glycan ligands for these CLRs were destroyed by PI treatment
We found that low concentrations of Allyl α-D-mannopyranoside (AllMan) blocked binding of both MR-Fc and DC-specific ICAM-3-grabbing non-integrin (DC-SIGN)-Fc to SEA (Fig 5D), whereas higher Methyl α-Dmannoside (MeMan) concentrations were needed to achieve a partial suppression of MR-Fc and DC-SIGN-Fc interaction with SEA

Summary

Introduction

Parasitic helminths (worms) have evolved to suppress inflammatory responses of the immune system to survive in their hosts [1]. These properties have equipped them with the PLOS ONE | DOI:10.1371/journal.pone.0124089. Several studies have shown that production of pro-inflammatory cytokines by TLR-stimulated human DCs is markedly reduced in response to direct contact with SEA [15,16,17]. Omega-1, a major component of SEA, can condition DCs into an anti-inflammatory phenotype with potential to induce a Th2 response, which is proposed to occur mainly via its RNase action [19,20].

Materials and Methods

Results

Discussion