Neuroprotective Effects of Polysialic Acid and SIGLEC-11 in Activated Phagocytic Cells

Abstract

SIGLEC-11 is an inhibitory receptor expressed on microglial cells and macrophages and can recognize α 2→8 linked Sias structures. The surface of neuron is decorated by different lengths of polySias. PolySia-SIGLEC-11 interaction is important to keep normal physiological conditions in neuron-microglia co-culture systems. However, till now it was not clear which length of polySia is recognized by SIGLEC-11.<br /> In this study the low molecular weight polySia with average degree of polymerization 20 (polySia avDP20), among different polySia lengths, introduced as the best length which was recognized by SIGLEC-11. PolySia avDP20 pre-treatment upon Aβ or debris stimulation kept superoxide release of microglia/macrophages as low as of untreated cells. This effect was not observed when cells were pre-treated with monoSia or oligoSias. Furthermore, compared to other polySia lengths (avDP60 and avDP180), polySia avDP20 had no effect on the metabolic activity of cells. Knockdown of SIGLEC-11 was enough to prevent the inhibitory function of polySia avDP20. Additional experiments showed that the anti-superoxide effect of polySia avDP20 was as potent as Trolox and SOD1. Phagocytosis analysis in iPSdM cells and macrophages revealed that polySia avDP20 pre-treatment did reduce uptake of Aβ and debris, which are inflammatory phagocytosis stimulants. Neurons were differentiated from pNSCs to investigate the consequence of polySia avDP20 addition to co-cultures with iPSdM/macrophages. Co-culture of Aβ or LPS stimulated iPSdM/macrophage with neurons led to shorter neurite length. This length could stay like untreated neurons if polySia avDP20 was present.<br /> Thus, this study suggests polySia avDP20 as a ligand for SIGLEC-11 receptor to reduce the inflammatory response of phagocytes towards provoking stimulants.