Klaver Elsenoor J, Kuijk Loes M, Lindhorst Thisbe K, Cummings Richard D, van Die Irma
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel, Kiel, Germany.
PLoS One. 2015 Apr 21;10(4):e0124089. doi: 10.1371/journal.pone.0124089. eCollection 2015.
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.
血吸虫病是（亚）热带地区一种常见的使人虚弱的人类寄生虫病，然而，血吸虫感染也可以预防多种炎症性疾病。这引发了人们对血吸虫将免疫系统调节为抗炎和调节状态的机制的广泛兴趣。人类树突状细胞（DCs）在与曼氏血吸虫可溶性虫卵抗原（SEA）接触后会出现许多表型变化。我们在此表明，SEA聚糖的氧化而非热变性会消除SEA抑制LPS诱导的细胞因子分泌和DC增殖的能力，这表明SEA聚糖在这些过程中起着重要作用。值得注意的是，SEA聚糖与DCs的相互作用导致细胞因子信号传导抑制因子1（SOCS1）和含SH2结构域的蛋白酪氨酸磷酸酶-1（SHP1）的表达显著增加，这是TLR4信号传导的重要负调节因子。此外，SEA诱导转化生长因子β（TGF-β）的分泌以及共刺激分子程序性死亡配体-1（PD-L1）和OX40配体（OX40L）的表面表达，这些是DCs将初始T细胞极化为Th2/Treg细胞亚群能力的已知表型标志物。用烯丙基α-D-甘露糖苷或抗MR抗体阻断甘露糖受体（MR）介导的SEA内化到DCs中，可显著降低SOCS1和SHP1的表达。总之，我们证明SEA聚糖对于通过MR诱导DCs中SOCS1和SHP1水平升高至关重要。我们的数据为曼氏血吸虫SEA聚糖调节人类DCs的潜力提供了新的机制证据，这可能有助于SEA下调炎症反应的能力。
