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 G N Garcia, Cynthia Wolberger, Nadia Raffaelli, Silvia Deaglio

Journal: Blood 2015;125(1):111-23

PMID: 25368373

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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 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.

Address: Department of Medical Sciences, University of Torino, Torino, Italy; Immunogenetics Unit, Human Genetics Foundation, Torino, Italy;; Department of Clinical Sciences, Università Politecnica delle Marche, Ancona, Italy;; Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy;; Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy;; Division of Hematology, Department of Translational Medicine, "A. Avogadro" University of Eastern Piedmont, Novara, Italy;; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD;; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY; Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, Torino, Italy; Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, NY;; Department of Pharmaceutical Sciences, "A. Avogadro" University of Eastern Piedmont, Novara, Italy;; Arizona Respiratory Center and Department of Medicine, The University of Arizona, Tucson, AZ; and.; Department of Agricultural, Food and Environmental Sciences, Università Politecnica delle Marche, Ancona, Italy.

DOI: 10.1182/blood-2014-07-589069