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Sialylation and Galectin-3 in Microglia-Mediated Neuroinflammation and Neurodegeneration
Mar Puigdellívol1, David H Allendorf1, Guy C Brown1
1Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Abstract:
Microglia are brain macrophages that mediate neuroinflammation and contribute to and protect against neurodegeneration. The terminal sugar residue of all glycoproteins and glycolipids on the surface of mammalian cells is normally sialic acid, and addition of this negatively charged residue is known as "sialylation," whereas removal by sialidases is known as "desialylation." High sialylation of the neuronal cell surface inhibits microglial phagocytosis of such neurons, via: (i) activating sialic acid receptors (Siglecs) on microglia that inhibit phagocytosis and (ii) inhibiting binding of opsonins C1q, C3, and galectin-3. Microglial sialylation inhibits inflammatory activation of microglia via: (i) activating Siglec receptors CD22 and CD33 on microglia that inhibit phagocytosis and (ii) inhibiting Toll-like receptor 4 (TLR4), complement receptor 3 (CR3), and other microglial receptors. When activated, microglia release a sialidase activity that desialylates both microglia and neurons, activating the microglia and rendering the neurons susceptible to phagocytosis. Activated microglia also release galectin-3 (Gal-3), which: (i) further activates microglia via binding to TLR4 and TREM2, (ii) binds to desialylated neurons opsonizing them for phagocytosis via Mer tyrosine kinase, and (iii) promotes Aβ aggregation and toxicity in vivo. Gal-3 and desialylation may increase in a variety of brain pathologies. Thus, Gal-3 and sialidases are potential treatment targets to prevent neuroinflammation and neurodegeneration.
Insights
Microglia
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, play a dual role in neuroinflammation and neurodegeneration.
- Cell surface sialylation normally inhibits microglial phagocytosis of neurons.
- Microglial sialylation also suppresses their inflammatory activation.
Purpose of the Study:
- To elucidate the mechanisms by which sialylation and desialylation influence microglial function in the brain.
- To investigate the role of galectin-3 (Gal-3) in microglial activation and neurodegeneration.
Main Methods:
- Analysis of sialylation and desialylation processes on neuronal and microglial cell surfaces.
- Investigation of microglial receptor-ligand interactions, including Siglecs, TLR4, and CR3.
- Assessment of galectin-3 (Gal-3) release and its effects on microglia and neurons.
Main Results:
- High neuronal sialylation inhibits microglial phagocytosis by engaging sialic acid receptors (Siglecs) and preventing opsonin binding.
- Microglial sialylation inhibits inflammatory activation via Siglec receptors (CD22, CD33) and other receptors like TLR4.
- Activated microglia release sialidase, desialylating cells and promoting microglial activation and neuronal phagocytosis.
- Activated microglia release Gal-3, which further activates microglia, opsonizes desialylated neurons for phagocytosis, and promotes Aβ aggregation.
Conclusions:
- Desialylation and Gal-3 increase in brain pathologies, suggesting their involvement in disease progression.
- Sialidases and Gal-3 represent potential therapeutic targets for preventing neuroinflammation and neurodegeneration.
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