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

• Published in: Journal of controlled release Vol. 338; pp. 680 - 693
• Main Authors: Bhattacherjee, Abhishek, Daskhan, Gour C., Bains, Arjun, Watson, Adrianne E.S., Eskandari-Sedighi, Ghazaleh, St. Laurent, Chris D., Voronova, Anastassia, Macauley, Matthew S.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 10.10.2021
• Subjects: Carbohydrates; CD33; Immune cell; Nanoparticles; Phagocytosis; Siglec; Nanoparticles; Carbohydrates; Siglec; CD33; Immune cell; Phagocytosis
• DOI: 10.1016/j.jconrel.2021.09.010
• ISSN: 0168-3659

CD33 is an immunomodulatory receptor expressed by 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 into transgenic mice expressing human CD33 in the microglial cell lineage 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. [Display omitted] •CD33 is a genetic risk factors for Alzheimer's disease susceptibility.•CD33 is an immunoinhibitory receptor expressed in brain microglia.•Liposomes displaying carbohydrate ligands were optimized for targeting CD33.•Liposomes targeting CD33 increase phagocytosis in microglial cells.•Liposomes delivered to transgenic mice expressing human CD33 are immunomodulatory.