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

Valentina Audrito, Sara Serra, Davide Brusa, Francesca Mazzola, Francesca Arruga, Tiziana Vaisitti, Marta Coscia, Rossana Maffei, Davide Rossi, Tao Wang, Giorgio Inghirami, Menico Rizzi, Gianluca Gaidano, Joe GN Garcia, Cynthia Wolberger, Nadia Raffaelli, Silvia Deaglio

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

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 kB (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-kB signaling; promote leukemic cell survival; and reduce T-cell responses. These effects are independent of the enzymaticactivity of NAMPT, asinferred from the use of anenzymatically inactive mutant. Overall, these results reveal that eNAMPT is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment of CLL.

Original languageEnglish (US)
Pages (from-to)111-123
Number of pages13
JournalBlood
Volume125
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

Audrito, V., Serra, S., Brusa, D., Mazzola, F., Arruga, F., Vaisitti, T., ... Deaglio, S. (2015). Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia. Blood, 125(1), 111-123. https://doi.org/10.1182/blood-2014-07-589069