Neuroimmunomodulatory properties of polysialic acid.

Polymeric sialic acid (polysialic acid, polySia) is a remarkable posttranslational modification of only few select proteins. The major, and most prominent polySia protein carrier is the neural cell adhesion molecule NCAM. Here, the key functions of polySia are to regulate interactions of NCAM and to balance cellular interactions in brain development and plasticity. During recent years, however, increasing evidence points towards a role of polySia in the modulation of immune responses. These immunomodulatory functions can be mediated by polySia on proteins other than NCAM, presented either on the cell surface or released into the extracellular space. This perspective review summarizes our current knowledge and addresses major open questions on polySia and polySia receptors in modulating innate immune responses in the brain.

Installation of high-affinity Siglec-1 ligand on tumor surface for macrophage-engaged tumor suppression.

Siglecs that binds cell surface sialoglycans are a family of immunomodulatory receptors, of which, Siglec-7 expressed on natural killer (NK) cells promotes tumor immunoevation while the role of Siglec-1 expressed on macrophages on tumor development remains largely unexplored. Herein, we selectively introduced high affinity sialoside ligands of Siglec-1 and Siglec-7 to tumor cell surface via in vivo Strain-promoted Azide-Alkyne cyclization of TCCSiaα2,3-Lactose or FITCSiaα2,6-Lactose with 9-azido sialic acid (AzSia) metabolically installed on tumor cell surface. We found that TCCSiaα2,3-Lactose conjugated on tumor surface moderately inhibited tumor growth while FITCSiaα2,6-Lactose promote tumor growth. These results suggest high-affinity ligand of Siglec-1 dispalyed on tumors surface provide a new perspective for tumor immunotherapy.

Immune Regulation in Eutherian Pregnancy: Live Birth Coevolved with Novel Immune Genes and Gene Regulation.

Novel regulatory elements that enabled expression of pre-existing immune genes in reproductive tissues and novel immune genes with pregnancy-specific roles in eutherians have shaped the evolution of mammalian pregnancy by facilitating the emergence of novel mechanisms for immune regulation over its course. Trade-offs arising from conflicting fitness effects on reproduction and host defenses have further influenced the patterns of genetic variation of these genes. These three mechanisms (novel regulatory elements, novel immune genes, and trade-offs) played a pivotal role in refining the regulation of maternal immune systems during pregnancy in eutherians, likely facilitating the establishment of prolonged direct maternal-fetal contact in eutherians without causing immunological rejection of the genetically distinct fetus.

Functions and therapeutic targets of Siglec-mediated infections, inflammations and cancers.

Siglecs, sialic acid (SA)-binding immunoglobulin (Ig)-like lectins, belong to a family of Ig-like lectins. All Siglecs have at least two domains including an extracellular domain with variable (V) and constant (C)-set immunoglobulin (Ig) regions, and a transmembrane domain. Some of the Siglecs (Siglec-2-12, -17, -E, -F and -G) with three domains including immunoreceptor tyrosine-based inhibitory motif associated with Src homology 2 (SH2) tyrosine phosphatases (SHP1/2) usually deliver an inhibitory signal. Certain Siglecs (Siglec-14, -15, -16 and -H) containing no intracellular domain carry certain basic amino acid in transmembrane domain coupled with immunoreceptor tyrosine-based activating motif for cell activation. The number of Siglec-encoding genes has been correlated to lifespan of mammals, indicating its evolutional advantage on acquisition of Siglecs in humans. Certain polymorphisms of Siglecs have been associated with premature delivery, infection, schizophrenia, allergy, dementia or chronic obstructive pulmonary disease. Siglecs mainly expressing on leukocytes could interact with cis- or trans-SA ligands for cell-cell and host-organism interactions on infections, inflammations and cancers. Amplifying or eliminating the SA-Siglec interactions is a promising strategy to treat cancers, infections and inflammations, based on SA modifications in different linkages or nanoparticle decoration, and on the antibodies in conjugation of chimeric receptor design or toxins.

News and Views on Polysialic Acid: From Tumor Progression and Brain Development to Psychiatric Disorders, Neurodegeneration, Myelin Repair and Immunomodulation.

Polysialic acid (polySia) is a sugar homopolymer consisting of at least eight glycosidically linked sialic acid units. It is a posttranslational modification of a limited number of proteins with the neural cell adhesion molecule NCAM being the most prominent. As extensively reviewed before, polySia-NCAM is crucial for brain development and synaptic plasticity but also modulates tumor growth and malignancy. Functions of polySia have been attributed to its polyanionic character, its spatial expansion into the extracellular space, and its modulation of NCAM interactions. In this mini-review, we first summarize briefly, how the modulation of NCAM functions by polySia impacts tumor cell growth and leads to malformations during brain development of polySia-deficient mice, with a focus on how the latter may be linked to altered behaviors in the mouse model and to neurodevelopmental predispositions to psychiatric disorders. We then elaborate on the implications of polySia functions in hippocampal plasticity, learning and memory of mice in light of recently described polySia changes related to altered neurogenesis in the aging human brain and in neurodegenerative disease. Furthermore, we highlight recent progress that extends the range of polySia functions across diverse fields of neurobiology such as cortical interneuron development and connectivity, myelination and myelin repair, or the regulation of microglia activity. We discuss possible common and distinct mechanisms that may underlie these seemingly divergent roles of polySia, and provide prospects for new therapeutic approaches building on our improved understanding of polySia functions.

Sialic Acid-Siglec-E Interactions During Pseudomonas aeruginosa Infection of Macrophages Interferes With Phagosome Maturation by Altering Intracellular Calcium Concentrations.

Pseudomonas aeruginosa (PA) is commonly associated with nosocomial and chronic infections of lungs. We have earlier demonstrated that an acidic sugar, sialic acid, is present in PA which is recognized and bound by sialic acid binding immunoglobulin type lectins (siglecs) expressed on neutrophils. Here, we have tried to gain a detailed insight into the immunosuppressive role of sialic acid-siglec interactions in macrophage-mediated clearance of sialylated PA (PA+Sia). We have demonstrated that PA+Sia shows enhanced binding (~1.5-fold) to macrophages due to additional interactions between sialic acids and siglec-E and exhibited more phagocytosis. However, internalization of PA+Sia is associated with a reduction in respiratory burst and increase in anti-inflammatory cytokines secretion which is reversed upon desialylation of the bacteria. Phagocytosis of PA+Sia is also associated with reduced intracellular calcium ion concentrations and altered calcium-dependent signaling which negatively affects phagosome maturation. Consequently, although more PA+Sia was localized in early phagosomes (Rab5 compartment), only fewer bacteria reach into the late phagosomal compartment (Rab7). Possibly, this leads to reduced phagosome lysosome fusion where reduced numbers of PA+Sia are trafficked into lysosomes, compared to PA-Sia. Thus, internalized PA+Sia remain viable and replicates intracellularly in macrophages. We have also demonstrated that such siglec-E-sialic acid interaction recruited SHP-1/SHP-2 phosphatases which modulate MAPK and NF-κB signaling pathways. Disrupting sialic acid-siglec-E interaction by silencing siglec-E in macrophages results in improved bactericidal response against PA+Sia characterized by robust respiratory burst, enhanced intracellular calcium levels and nuclear translocation of p65 component of NF-κB complex leading to increased pro-inflammatory cytokine secretion. Taken together, we have identified that sialic acid-siglec-E interactions is another pathway utilized by PA in order to suppress macrophage antimicrobial responses and inhibit phagosome maturation, thereby persisting as an intracellular pathogen in macrophages.

Sialylated Cervical Mucins Inhibit the Activation of Neutrophils to Form Neutrophil Extracellular Traps in Bovine in vitro Model.

In order to combat invading pathogens neutrophils can release neutrophil extracellular traps (NETs). However, since NETs can also damage endogenous cells, several control mechanisms for the formation of NETs must work effectively. For instance, neutrophil activation is silenced within blood circulation by the binding of sialylated glycoconjugates to sialic acid binding immunoglobulin-like lectins (Siglecs) on neutrophils. As neutrophils are recruited within the female reproductive tract, after mating, a comparable mechanism may also take place within the bovine cervix to prevent an exaggerated NET formation and thus, infertility. We examined, if the highly glycosylated mucins, which are the major functional fraction of biomolecules in mucus, represent a potential regulator of NET formation. The qPCR data revealed that in polymorphonuclear neutrophils (PMNs) inhibitory Siglecs are the most frequently expressed Siglecs and might be a potential target of sialylated glycans to modulate the activation of PMNs. Remarkably, the addition of bovine cervical mucins significantly inhibited the formation of NET, which had been induced in response to lipopolysaccharides (LPS) or a combination of phorbol myristate acetate (PMA) and ionomycin. The inhibitory effects were independent of the stage of estrous cycle (estrus, luteal, and follicular mucins). PMNs retained their segmented nuclei and membrane perforation was prevented. However, the inhibitory effects were diminished, when sialic acids were released under acidic conditions. Comparable results were achieved, when sialic acids were targeted by neuraminidase digestion, indicating a sialic acid dependent inhibition of NET release. Thus, bovine cervical mucins have an anti-inflammatory capability to modulate NET formation and might be further immunomodulatory biomolecules that support fertility.

The Role of Siglecs in Immune Signaling Regulation and Immune Pathology / 中国生物化学与分子生物学报

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are members of the immunoglobulin superfamily expressed in most white blood cells of the immune system. The Siglec is a kind of transmembrane proteins that can recognize sialic acid-containing ligands, and it is the most important subgroup of type I lectin. All Siglecs contain at least three domains, including the V-set Ig domain, C2-set Ig domain and transmembrane domain. Some Siglecs contain immune receptor tyrosine-based inhibitory motifs (ITIMs), which are used to transmit inhibitory signals and play an inhibitory role. There are also some Siglecs that do not contain intracellular domains, and they can transmit activation signals through basic amino acids in transmembrane domains to play an activation role. Siglecs not only participate in the regulation of activation, proliferation and apoptosis of immune cells, but also help the immune system to distinguish itself from non-itself by recognizing glycan ligands containing sialic acid. In recent years, studies have shown that Siglecs, as an immune checkpoint, play an important role in the immune regulation in human diseases such as cancer, asthma, allergy, Alzheimer’s disease and autoimmune diseases, and it has received extensive attention. Enhancing or blocking the interaction of sialic acid with Siglecs is an effective strategy for the treatment of cancer, infection, and other diseases. In this review, we describe the classification of Siglecs, their expression in different immune cells and their role in the regulation of immune cell signaling. Emphasis was placed on the role of Siglecs in disease and methods of targeting Siglecs for the treatment of human diseases.