Regulation of Phagocytosis in Macrophages by Neuraminidase 1

Abstract

The differentiation of monocytes into macrophages and dendritic cells is accompanied by induction of cell-surface neuraminidase 1 (Neu1) and cathepsin A (CathA), the latter forming a complex with and activating Neu1. To clarify the biological importance of this phenomenon we have developed the gene-targeted mouse models of a CathA deficiency (CathA S190A ) and a double CathA/Neu1 deficiency (CathA S190A-Neo ). Macrophages of CathA S190A-Neo mice and their immature dendritic cells showed a significantly reduced capacity to engulf Grampositive and Gram-negative bacteria and positively and negatively charged polymer beads as well as IgG-opsonized beads and erythrocytes. Properties of the cells derived from CathA S190A mice were indistinguishable from those of wild-type controls, suggesting that the absence of Neu1, which results in the increased sialylation of the cell surface proteins, probably affects multiple receptors for phagocytosis. Previous data showed that mammalian neuraminidase 1 (Neu1), 5 in addition to its role in the intralysosomal catabolism, may be also involved in cellular signaling during the immune response. In particular, during the activation of mouse T cells, Neu1 is expressed on the plasma membrane and is required for the early production of interleukin-4 and for the interaction of T cells with the antigen-presenting cells (8 -12). In addition, Neu1 of T cells converts the group-specific component (Gc protein) into a factor necessary for the inflammation-primed activation of macrophages (13,14). T cells derived from SM/J or B10.SM strains of mice with the reduced Neu1 activity, due to a missense mutation in the Neu1 gene (15), fail to convert Gc and synthesize interleukin-4, whereas B cells of these mice cannot produce IgG 1 and IgE after immunization with pertussis toxin (8,14,16). Strikingly, surface desialylation of macrophages by viral sialidase from Arthrobacter ureafaciens significantly increases their capacity for phagocytosis of influenza virus-infected HeLa cells (17), providing the direct link between the surface sialylation of antigen-presenting cells and their biological activity.Previously we showed that Neu1 increased 14-fold during the differentiation of human monocytes into macrophages (18). * This work was supported in part by Canadian Institutes of Health ResearchOperating Grants MOP 15079 and GOP 38107 and by an equipment grant from Canadian Foundation for Innovation (to A. V. P.

Change of Transferrin Sialylation Differs between Mild Sepsis and Severe Sepsis and Septic Shock

“…Increased neuraminidase activity was previously suggested as the most probable mechanism (20). It was recently shown that neuraminidase activity increases in sepsis which leads to erythrocyte desialylation (35) and that neuraminidase 1, one of the four human neuraminidases, has an important role in the immune response and inflammation (36)(37)(38)(39). However, the present re- sults show that, in contrast to transferrin, total plasma proteins do not show a decrease in their sialylation levels.…”

Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9

“…In another study, Neu1 was found to negatively regulate lysosomal exocytosis in hematopoietic cells where it processes the sialic acids on the lysosomal membrane protein LAMP-1 [24]. More recently, evidence is provided to suggest that cell surface Neu1 also activates phagocytosis in macrophages and dendritic cells presumably through the desialylation of multiple receptors, including Fc receptors for immunoglobulin G (FcγR) [58].…”

Macrophages Discriminate Glycosylation Patterns of Apoptotic Cell-derived Microparticles

“…This suggests the action of a cell surface-linked sialidase like Neu-3 (18) or the reportedly surface associated Neu-1 (19). Antisera directed against peptides of Neu-1 and Neu-3 diminished surface-associated sialidase activity (not shown).…”