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.

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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