Increasing phagocytosis of microglia through targeting CD33 with liposomes displaying glycan ligands

Abstract

CD33 is an immunomodulatory receptor expressed on microglia and genetically linked to Alzheimer's disease (AD) susceptibility. While antibodies targeting CD33 have entered clinical trials to treat neurodegeneration, it is unknown whether the glycan-binding properties of CD33 can be exploited to modulate microglia. Here, we use liposomes that multivalently display glycan ligands of CD33 (CD33L liposomes) to engage CD33. We find that CD33L liposomes increase phagocytosis of cultured monocytic cells and microglia in a CD33-dependent manner. Enhanced phagocytosis strongly correlates with loss of CD33 from the cell surface and internalization of liposomes. Increased phagocytosis by treatment with CD33L liposomes is dependent on a key intracellular signaling motif on CD33 as well as the glycan-binding ability of CD33. These effects are specific to trans engagement of CD33 by CD33L liposomes, as cis engagement through insertion of lipid-linked CD33L into cells produces the opposite effect on phagocytosis. Moreover, intracerebroventricular injection of CD33L liposomes in mice enhances phagocytosis of microglia in a CD33-dependent manner. These results demonstrate that multivalent engagement of CD33 with glycan ligands can modulate microglial cell function.

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

“…For instance, liposomes coated with 1, a sialylated oligosaccharide that binds to SIGLEC-3/CD33, was shown to reduce cell surface expression of SIGLEC-3 by internalization. This approach led to increased phagocytosis by microglia in transgenic mice expressing human SIGLEC-3 (147). Consequently, the concept of inhibiting the suppressive activity of SIGLEC-3 in the brains of AD patients to enhance microglial-mediated clearance of amyloid-β plaques was tested in preclinical and clinical settings.…”