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.
Highlights
Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunomodulatory receptors with many ascribed roles in controlling immune cell function in health and disease[1]
Our findings demonstrate that expression of the long isoform of human CD33 (hCD33) alone is sufficient to repress phagocytosis in both monocytes and microglia
Our transgenic mice expressing hCD33M will be a valuable tool for future studies addressing the role of hCD33 in modulating plaque accumulation as well as preclinical testing of therapeutics aimed at targeting hCD33
Summary
Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunomodulatory receptors with many ascribed roles in controlling immune cell function in health and disease[1]. Siglecs can act as either positive or negative regulators of immune cell signaling, which is primarily dictated by two residues The first of these key residues is one or more tyrosines in the cytoplasmic tail that are contained within an immunoreceptor tyrosine-based inhibitory motif (ITIM). A second mutually exclusive key residue is a positively charged lysine or arginine in the transmembrane region in certain Siglec family members, which serves to pair Siglecs with an aspartic acidcontaining adaptor protein, such as Dap[12] These adaptor proteins have immunoreceptor tyrosine-based activatory motifs (ITAMs)[6,7], suggesting that Siglecs that pair with Dap[12] have the potential to be activatory. Contains a cytidine near the start of exon 2, while the less common CD33 protective allele (rs12459419T) has a thymidine
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