Sialylation acts as a checkpoint for innate immune responses in the central nervous system

Abstract

Sialic acids are monosaccharides that normally terminate the glycan chains of cell surface glyco‐proteins and ‐lipids in mammals, and are highly enriched in the central nervous tissue. Sialic acids are conjugated to proteins and lipids (termed “sialylation”) by specific sialyltransferases, and are removed (“desialylation”) by neuraminidases. Cell surface sialic acids are sensed by complement factor H (FH) to inhibit complement activation or by sialic acid‐binding immunoglobulin‐like lectin (SIGLEC) receptors to inhibit microglial activation, phagocytosis, and oxidative burst. In contrast, desialylation of cells enables binding of the opsonins C1, calreticulin, galectin‐3, and collectins, stimulating phagocytosis of such cells. Hypersialylation is used by bacteria and cancers as camouflage to escape immune recognition, while polysialylation of neurons protects synapses and neurogenesis. Insufficient lysosomal cleavage of sialylated molecules can lead to lysosomal accumulation of lipids and aggregated proteins, which if excessive may be expelled into the extracellular space. On the other hand, desialylation of immune receptors can activate them or trigger removal of proteins. Loss of inhibitory SIGLECs or FH triggers reduced clearance of aggregates, oxidative brain damage and complement‐mediated retinal damage. Thus, cell surface sialylation recognized by FH, SIGLEC, and other immune‐related receptors acts as a major checkpoint inhibitor of innate immune responses in the central nervous system, while excessive cleavage of sialic acid residues and consequently removing this checkpoint inhibitor may trigger lipid accumulation, protein aggregation, inflammation, and neurodegeneration.

Low molecular weight polysialic acid prevents lipopolysaccharide‐induced inflammatory dopaminergic neurodegeneration in humanized SIGLEC11 transgenic mice

“…Thus, our findings support the concept that the SIGLEC receptors bearing inhibitory ITIMs (e.g. human SIGLEC11 and mouse SIGLEC‐E) negatively regulate activatory ITAM‐domain receptor‐associated inflammatory and phagocytosis processes (Klaus et al, 2020; H. Liao et al, 2020).…”

Increased Transferrin Sialylation Predicts Phenoconversion in IsolatedREMSleep Behavior Disorder

“…Cell‐surface sialylation acts as an immune checkpoint 41 . Sialic acid–binding immunoglobulin‐type lectins (Siglecs) expressed on leukocytes recognize sialic acid–containing glycans as ligands.…”

“…Sialic acid–binding immunoglobulin‐type lectins (Siglecs) expressed on leukocytes recognize sialic acid–containing glycans as ligands. Microglial Siglec receptors inhibit microglial activation, inflammation, phagocytosis, and oxidative burst 41 . Siglec‐E knock‐out mice demonstrated higher oxidative damage, 42 and the deletion of Siglec‐E's counterbalancing receptor led to decreased age‐related inflammatory signs and neuronal loss 43 .…”

Polysialic Acid in the Immune System

“…Microglial cells play a pivotal role in brain development, maturation, and homeostasis by responding to infection, trauma, or other pathological conditions, transforming into macrophage-like cells with a professional innate immune defense function that can be regulated by sialylation (164)(165)(166). Sialic acids maintain the homeostasis of the CNS innate immune response by inhibiting complement, including microglia via Siglecs and other receptors (167).…”