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Updated: Jan 2, 2026
A Quantitative Assessment of the Phagocytosis of Allogeneic and Xenogeneic Erythrocytes by Rat Macrophages In Vitro
Published on: August 22, 2025
Repression of phagocytosis by human CD33 is not conserved with mouse CD33
Abhishek Bhattacherjee1, Emily Rodrigues1, Jaesoo Jung1
11Department of Chemistry, University of Alberta, Alberta, Canada.
Abstract:
CD33 is an immunomodulatory receptor linked to Alzheimer's disease (AD) susceptibility via regulation of phagocytosis in microglia. Divergent features between human CD33 (hCD33) and murine CD33 (mCD33) include a unique transmembrane lysine in mCD33 and cytoplasmic tyrosine in hCD33. The functional consequences of these differences in restraining phagocytosis remains poorly understood. Using a new αmCD33 monoclonal antibody, we show that mCD33 is expressed at high levels on neutrophils and low levels on microglia. Notably, cell surface expression of mCD33 is entirely dependent on Dap12 due to an interaction with the transmembrane lysine in mCD33. In RAW264.7 cultured macrophages, BV-2 cultured microglia, primary neonatal and adult microglia, uptake of cargo - including aggregated Aβ1-42 - is not altered upon genetic ablation of mCD33. Alternatively, deletion of hCD33 in monocytic cell lines increased cargo uptake. Moreover, transgenic mice expressing hCD33 in the microglial cell lineage showed repressed cargo uptake in primary microglia. Therefore, mCD33 and hCD33 have divergent roles in regulating phagocytosis, highlighting the importance of studying hCD33 in AD susceptibility.
Insights
Murine CD33 (mCD33) does not regulate microglial phagocytosis, unlike human CD33 (hCD33). This difference is crucial for understanding Alzheimer's disease (AD) susceptibility and developing targeted therapies.
Area of Science:
- Immunology
- Neuroscience
- Genetics
Background:
- CD33 is an immunomodulatory receptor implicated in Alzheimer's disease (AD) susceptibility.
- Microglial phagocytosis is a key process regulated by CD33.
- Human CD33 (hCD33) and murine CD33 (mCD33) exhibit structural differences, particularly in their transmembrane and cytoplasmic domains, suggesting functional divergence.
Purpose of the Study:
- To investigate the functional consequences of structural differences between hCD33 and mCD33 on phagocytosis.
- To determine the role of mCD33 in regulating microglial phagocytic activity.
- To compare the effects of mCD33 and hCD33 on the uptake of aggregated amyloid-beta (Aβ) species.
Main Methods:
- Utilized a novel αmCD33 monoclonal antibody for expression analysis.
- Employed genetic ablation of mCD33 in various cell lines (RAW264.7 macrophages, BV-2 microglia, primary neonatal and adult microglia).
- Generated transgenic mice expressing hCD33 in the microglial lineage for in vivo studies.
Main Results:
- mCD33 is highly expressed on neutrophils and lowly on microglia, with cell surface expression dependent on Dap12 via its transmembrane lysine.
- Genetic deletion of mCD33 did not alter cargo uptake in various microglial and macrophage models.
- Deletion of hCD33 in monocytic cells increased cargo uptake, and hCD33 expression in microglia repressed cargo uptake.
Conclusions:
- mCD33 and hCD33 play divergent roles in regulating phagocytosis.
- hCD33, but not mCD33, restrains phagocytic activity in microglia.
- These findings underscore the importance of studying hCD33 in the context of Alzheimer's disease pathogenesis.
