Unusual Properties of a Human‐specific and Microglia‐specific Siglec‐11 Transcript Variant

Abstract

CD33‐related sialic acid‐binding immunoglobulin‐type lectins (Siglecs) are often found on innate immune cells and can modulate their reactivity. Previous studies showed that expression of the inhibitory Siglec‐11 in microglia is unique to humans and exists as an alternate splice form missing the exon encoding the last (5th) Ig‐like C2 set domain of the extracellular portion of the protein. Moreover, the brain‐enriched glycan polysialic acid (polySia/PSA) has been considered as a ligand of Siglec‐11. Here, we show that the human recombinant soluble microglial form hSiglec‐11(4D)‐Fc binds better to immobilized polySia than the tissue macrophage form hSiglec‐11(5D)‐Fc or chimpanzee cSiglec‐11(5D)‐Fc. We found that both intact and cleaved Siglec‐11 are in the culture medium, suggesting their ability to be secreted. Specifically, intact Siglec‐11 is found in exosomes and the microglial splice variant has reduced proteolytic cleavage and enhanced incorporation into exosomes. The exosomes bind to human neuroblastoma in a polySia‐dependent fashion. Mechanistically, cysteine palmitoylation is observed in the intracellular region and may regulate Siglec‐11 localization on lipid rafts and secretion on exosomes. Taken together, we demonstrate that hSiglec‐11(4D) is specifically expressed in human brain microglia and is released on the exosomes and/or proteolytic products, which have the potential to affect brain functions at a distance.Support or Funding InformationNational Institute of General Medical Sciences (NIGMS) R01GM32373