The Roles of Siglec7 and Siglec9 on Natural Killer Cells in Virus Infection and Tumour Progression.

The function of natural killer (NK) cells, defending against virus infection and tumour progression, is regulated by multiple activating and inhibiting receptors expressed on NK cells, among which sialic acid-bind immunoglobulin-like lectins (Siglecs) act as a vital inhibitory group. Previous studies have shown that Siglec7 and Siglec9 are expressed on NK cells, which negatively regulate the function of NK cells and modulate the immune response through the interaction of sialic acid-containing ligands. Siglec7 and Siglec9 are very similar in distribution, gene encoding, protein sequences, ligand affinity, and functions in regulating the immune system against virus and cancers, but differences still exist between them. In this review, we aim to discuss the similarities and differences between Siglec7 and Siglec9 and analyze their functions in virus infection and tumour progression in order to develop better anti-viral and anti-tumor immunotherapy in the future.

Reduced sialylation triggers homeostatic synapse and neuronal loss in middle-aged mice.

Sialic acid-binding Ig-like lectin (Siglec) receptors are linked to neurodegenerative processes, but the role of sialic acids in physiological aging is still not fully understood. We investigated the impact of reduced sialylation in the brain of mice heterozygous for the enzyme glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE+/-) that is essential for sialic acid biosynthesis. We demonstrate that GNE+/- mice have hyposialylation in different brain regions, less synapses in the hippocampus and reduced microglial arborization already at 6 months followed by increased loss of neurons at 12 months. A transcriptomic analysis revealed no pro-inflammatory changes indicating an innate homeostatic immune process leading to the removal of synapses and neurons in GNE+/- mice during aging. Crossbreeding with complement C3-deficient mice rescued the earlier onset of neuronal and synaptic loss as well as the changes in microglial arborization. Thus, sialic acids of the glycocalyx contribute to brain homeostasis and act as a recognition system for the innate immune system in the brain.

Siglecs in Brain Function and Neurological Disorders.

Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and generate activating or inhibitory signals. They are also shown to be expressed on the surface of cells in the nervous system and have been shown to play central roles in neuroinflammation. There has been a plethora of reviews outlining the studies pertaining to Siglecs in immune cells. However, this review aims to compile the articles on the role of Siglecs in brain function and neurological disorders. In humans, the most abundant Siglecs are CD33 (Siglec-3), Siglec-4 (myelin-associated glycoprotein/MAG), and Siglec-11, Whereas in mice the most abundant are Siglec-1 (sialoadhesin), Siglec-2 (CD22), Siglec-E, Siglec-F, and Siglec-H. This review is divided into three parts. Firstly, we discuss the general biological aspects of Siglecs that are expressed in nervous tissue. Secondly, we discuss about the role of Siglecs in brain function and molecular mechanism for their function. Finally, we collate the available information on Siglecs and neurological disorders. It is intriguing to study this family of proteins in neurological disorders because they carry immunoinhibitory and immunoactivating motifs that can be vital in neuroinflammation.

Preferential use of Siglec-1 or Siglec-10 by type 1 and type 2 PRRSV strains to infect PK15S1-CD163 and PK15S10-CD163 cells.

Cellular entry mediators define whether the cell is permissive to PRRSV infection. Porcine sialoadhesin (pSn, Siglec-1) and CD163 are main entry mediators facilitating infection of porcine macrophages by PRRSV. Recently, Siglec-10 was demonstrated to be an alternative receptor for PRRSV. To examine if virulence and pathogenicity of PRRSV strains could be correlated with the use of different Siglecs, a PK15 cell line recombinantly expressing Siglec-1 and CD163 (PK15S1-CD163) and a PK15 cell line recombinantly expressing Siglec-10 and CD163 (PK15S10-CD163) were used to compare the virus replication of 7 genotype 1 subtype 1 strains (G1s1), 2 genotype 1 subtype 3 (G1s3) strains and 5 genotype 2 (G2) strains. Some strains (08VA (G1s1), 13V117 (G1s1), 17V035 (G1s1), VR2332 (G2)) were poor virus producers (<104 TCID50/mL), while other strains (07V063 (G1s1), 13V091 (G1s1), Su1-Bel (G1s3), MN-184 (G2), Korea17 (G2) and SDSU-73 (G2)) easily grew up to ≥106 TCID50/mL. PK15S10-CD163 cells exhibited a higher efficiency in virus production per infected cell than the PK15S1-CD163 cells. The G1s1 strains LV and 07V063 infected more cells in the PK15S1-CD163, whereas the 94V360 and 08VA strains preferred PK15S10-CD163. The highly virulent G1s3 strains Lena and Su1-Bel showed a strong preference for PK15S1-CD163. The G2 strains MN-184, SDSU-73, Korea17 had a much higher infection rate in PK15S10-CD163, while the reference strain VR2332 and the NADC30 strain had a slight preference for PK15S1-CD163. Differences in receptor use may influence the outcome of a PRRSV infection in pigs and explain in part the virulence/pathogenicity of PRRSV strains.

The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease.

A high proportion of peripheral human B cells produce polyreactive or autoreactive antibodies, which indicates that they have escaped the elimination of self-reactive B cells in the bone marrow. CD22 and Siglec-G are two inhibitory receptors of the sialic-acid-binding immunoglobulin-like lectin (Siglec) family that inhibit the B-cell antigen receptor (BCR) signal. The ability of these two receptors to bind sialic acids is crucial for regulating inhibition and inducing tolerance to self-antigens. Sialylated glycans are usually absent on microbes (although several pathogenic microorganisms have evolved strategies to mimic self by decorating their surfaces with sialic acids) but abundant in higher vertebrates and might, therefore, provide an important tolerogenic signal. Combined Siglec-G deficiency and CD22 deficiency leads to spontaneous autoimmunity in mice, and mutations in an enzyme that modifies Siglec ligands are directly linked to several autoimmune diseases in humans. New data show that high-affinity ligands for CD22 and Siglec-G can be used to induce antigen-specific B-cell tolerance, which might be one strategy for the treatment of autoimmune diseases in the future.

Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion.

The increase of cell surface sialic acid is a characteristic shared by many tumor types. A correlation between hypersialylation and immunoprotection has been observed, but few hypotheses have provided a mechanistic understanding of this immunosuppressive phenomenon. Here, we show that increasing sialylated glycans on cancer cells inhibits human natural killer (NK) cell activation through the recruitment of sialic acid-binding immunoglobulin-like lectin 7 (Siglec-7). Key to these findings was the use of glycopolymers end-functionalized with phospholipids, which enable the introduction of synthetically defined glycans onto cancer cell surfaces. Remodeling the sialylation status of cancer cells affected the susceptibility to NK cell cytotoxicity via Siglec-7 engagement in a variety of tumor types. These results support a model in which hypersialylation offers a selective advantage to tumor cells under pressure from NK immunosurveillance by increasing Siglec ligands. We also exploited this finding to protect allogeneic and xenogeneic primary cells from NK-mediated killing, suggesting the potential of Siglecs as therapeutic targets in cell transplant therapy.