Anti-inflammatory activity of low molecular weight polysialic acid on human macrophages.

Anahita Shahraz,Joachim Kappler,Harald Neumann,Thomas Scheper,Dominic Winter,Rene Mathy,Volkmar Gieselmann,Jens Kopatz,Shoba Kapoor,Vlad Schütza

doi:10.1038/srep16800

Abstract

Oligosialic and polysialic acid (oligoSia and polySia) of the glycocalyx of neural and immune cells are linear chains, in which the sialic acid monomers are α2.8-glycosidically linked. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a primate-lineage specific receptor of human tissue macrophages and microglia that binds to α2.8-linked oligoSia. Here, we show that soluble low molecular weight polySia with an average degree of polymerization 20 (avDP20) interacts with SIGLEC-11 and acts anti-inflammatory on human THP1 macrophages involving the SIGLEC-11 receptor. Soluble polySia avDP20 inhibited the lipopolysaccharide (LPS)-induced gene transcription and protein expression of tumor necrosis factor-α (Tumor Necrosis Factor Superfamily Member 2, TNFSF2). In addition, polySia avDP20 neutralized the LPS-triggered increase in macrophage phagocytosis, but did not affect basal phagocytosis or endocytosis. Moreover, polySia avDP20 prevented the oxidative burst of human macrophages triggered by neural debris or fibrillary amyloid-β1–42. In a human macrophage-neuron co-culture system, polySia avDP20 also reduced loss of neurites triggered by fibrillary amyloid-β1–42. Thus, treatment with polySia avDP20 might be a new anti-inflammatory therapeutic strategy that also prevents the oxidative burst of macrophages.

Highlights

PolySia expression is tightly linked with the level of expressed polysialyltransferases[6] and membrane associated neuraminidases[5]
OligoSia in form of α 2.8-linked sialic acid (Sia) has been shown to bind to SIGLEC-11 receptors that are expressed on human tissue macrophages and microglia[1,2], but the interaction of SIGLEC-11 with soluble polysialic acid (polySia) has not been analyzed
We show that low molecular weight polySia acted anti-inflammatory on human THP1 macrophages by inhibiting the LPS-induced gene transcription and protein secretion of TNFSF2 and by preventing the oxidative burst associated with phagocytosis of debris or fibrillary amyloid-β 1–42

Summary

Introduction

PolySia expression is tightly linked with the level of expressed polysialyltransferases[6] and membrane associated neuraminidases[5]. By means of molecular mimicry the polySia coat supports escape of bacteria from immune recognition. We analyzed the effect of soluble low molecular weight polySia on human SIGLEC-11 expressing THP1 cell derived macrophages. Low molecular weight polySia with an average DP20 exhibited an anti-inflammatory effect that was inhibited by a knock-down of the SIGLEC-11 receptor. Low molecular weight polySia inhibited inflammatory phagocytosis without affecting basal phagocytosis and endocytosis. Low molecular weight polySia completely prevented the phagocytosis associated oxidative burst of human macrophages. In a human macrophage-neuron co-culture system, polySia avDP20 inhibited the radical mediated neurotoxicity triggered by fibrillary amyloid-β 1–42

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Results

Conclusion