Activation of the Intracellular Pattern Recognition Receptor NOD2 Promotes Acute Myeloid Leukemia (AML) Cell Apoptosis and Provides a Survival Advantage in an Animal Model of AML
Autor: | Anasuya Sarkar, Rakesh A Murugesan, Giovanna Merchand-Reyes, John C. Byrd, Sumithira Vasu, Jonathan P. Butchar, Susheela Tridandapani, Gino M Dettorre, Bethany L. Mundy-Bosse, Nathaniel J Buteyn, Ramasamy Santhanam |
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Rok vydání: | 2020 |
Předmět: |
Myeloid
Immunology Nod2 Signaling Adaptor Protein Apoptosis Biology Article Interferon-gamma Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor NOD2 medicine Animals Humans Immunology and Allergy Receptor Innate immune system Pattern recognition receptor Myeloid leukemia digestive system diseases Tumor Necrosis Factor Receptor Superfamily Member 7 Mice Inbred C57BL Disease Models Animal Leukemia Myeloid Acute medicine.anatomical_structure chemistry Receptors Pattern Recognition Cancer research Signal transduction Muramyl dipeptide Signal Transduction 030215 immunology |
Zdroj: | J Immunol |
ISSN: | 1550-6606 0022-1767 |
Popis: | TLRs, a family of membrane-bound pattern recognition receptors found on innate immune cells, have been well studied in the context of cancer therapy. Activation of these receptors has been shown to induce inflammatory anticancer events, including differentiation and apoptosis, across a wide variety of malignancies. In contrast, intracellular pattern recognition receptors such as NOD-like receptors have been minimally studied. NOD2 is a member of the NOD-like receptor family that initiates inflammatory signaling in response to the bacterial motif muramyl dipeptide. In this study, we examined the influence of NOD2 in human acute myeloid leukemia (AML) cells, demonstrating that IFN-γ treatment upregulated the expression of NOD2 signaling pathway members SLC15A3 and SLC15A4, downstream signaling kinase RIPK2, and the NOD2 receptor itself. This priming allowed for effective induction of caspase-1–dependent cell death upon treatment with muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic ligand for NOD2. Furthermore, the combination of MTP-PE and IFN-γ on AML blasts generated an inflammatory cytokine profile and activated NK cells. In a murine model of AML, dual treatment with MTP-PE and IFN-γ led to a significant increase in mature CD27− CD11b+ NK cells as well as a significant reduction in disease burden and extended survival. These results suggest that NOD2 activation, primed by IFN-γ, may provide a novel therapeutic option for AML. |
Databáze: | OpenAIRE |
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