Knockout of sialoadhesin enhances microglial accumulation during prion pathogenesis

Objective: The adhesion molecule sialoadhesin (Sialic acid-binding Ig-like lectin 1 [Siglec-1], CD169) binds sialic acid residues of glycoproteins and promotes endocytosis. Sialoadhesin is constitutively expressed by splenic marginal zone or lymph node subcapsular sinus macrophages which function to trap immune complexes. Sialoadhesin expression may also be induced in myeloid lineage cells upon exposure to blood-borne cytokines. The prion glycoprotein is heavily sialylated and may act as a ligand for sialoadhesin. To determine if sialoadhesin played a role in the uptake and pathogenesis of prion infectious-agent, scrapie challenge studies were performed in sialoadhesin–deficient (SnKO) transgenic mice.
Material and Methods: Groups of SnKO mice and C57Bl/6 control mice were inoculated intracerebrally or intraperitoneally with mouse adapted scrapie agent ME7. Mice were studied at 5, 10 and 15 weeks for peripheral prion pathogenesis following intraperitoneal inoculation.
Results: Following intraperitoneal infection SnKO mice revealed no significant differences to C57Bl/6 mice in all aspects studied, including assessment of immune function via antigen trapping assays and disease-associated PrP accumulation in lymphoid follicles. Following intracerebral infection alterations were observed in brain region-specific microglial responses resulting in elevated levels of disease-associated vacuolation in hippocampal CA1 region and enhanced microglial proliferation and accumulation into multi-cellular aggregates.
Conclusions: The removal of sialoadhesin expression did not affect the peripheral pathogenesis of prion disease, therefore sialoadhesin is not required for the sequestration of the prion infectious agent into lymphoid germinal centres. Following intracerebral infection sialoadhesin-deficient mice displayed enhanced microglial response and proliferation in specific brain regions. These data suggest that the knockout of sialoadhesin may have altered microglial cell-cell recognition resulting in microglial multicellular aggregates. Alternatively damage to the blood brain barrier following intracerebral inoculation may have altered the priming of sialoadhesin-deficient microglia, leading to an enhanced pro-inflammatory response during infection and an increase in microglial proliferation.