Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia.

TitleExtracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia.
Publication TypeJournal Article
Year of Publication2015
AuthorsAudrito V, Serra S, Brusa D, Mazzola F, Arruga F, Vaisitti T, Coscia M, Maffei R, Rossi D, Wang T, Inghirami G, Rizzi M, Gaidano G, Garcia JGN, Wolberger C, Raffaelli N, Deaglio S
JournalBlood
Volume125
Issue1
Pagination111-23
Date Published2015 Jan 01
ISSN Number1528-0020
KeywordsAged, Antigens, CD, Antigens, Differentiation, Myelomonocytic, B-Lymphocytes, Blood Donors, Cell Differentiation, Cell Proliferation, Cell Survival, Enzyme-Linked Immunosorbent Assay, Female, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Interleukin-10, Lectins, C-Type, Leukemia, Lymphocytic, Chronic, B-Cell, Macrophages, Male, Mannose-Binding Lectins, Microscopy, Confocal, Monocytes, Mutation, NF-kappa B, Nicotinamide Phosphoribosyltransferase, Phagocytosis, Receptors, Cell Surface, STAT3 Transcription Factor
Abstract

<p>Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis. In the extracellular compartment, it exhibits cytokine-/adipokinelike properties, suggesting that it stands at the crossroad between metabolism and inflammation. Here we show that both intracellular and extracellular NAMPT levels are increased in cells and plasma of chronic lymphocytic leukemia (CLL) patients. The extracellular form (eNAMPT) is produced by CLL lymphocytes upon B-cell receptor, Toll-like receptor, and nuclear factor κB (NF-κB) signaling pathway activation. eNAMPT is important for differentiation of resting monocytes, polarizing them toward tumor-supporting M2 macrophages. These cells express high levels of CD163, CD206, and indoleamine 2,3-dioxygenase and secrete immunosuppressive (interleukin [IL] 10, CC chemokine ligand 18) and tumor-promoting (IL-6, IL-8) cytokines. NAMPT-primed M2 macrophages activate extracellular-regulated kinase 1/2, signal transducer and activator of transcription 3, and NF-κB signaling; promote leukemic cell survival; and reduce T-cell responses. These effects are independent of the enzymatic activity of NAMPT, as inferred from the use of an enzymatically inactive mutant. Overall, these results reveal that eNAMPT is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment of CLL.</p>

DOI10.1182/blood-2014-07-589069
Alternate JournalBlood
PubMed ID25368373