Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
Bruzzone
Santina
S
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Genoa, Italy.
Fruscione
Floriana
F
Morando
Sara
S
Ferrando
Tiziana
T
Poggi
Alessandro
A
Garuti
Anna
A
D'Urso
Agustina
A
Selmo
Martina
M
Benvenuto
Federica
F
Cea
Michele
M
Zoppoli
Gabriele
G
Moran
Eva
E
Soncini
Debora
D
Ballestrero
Alberto
A
Sordat
Bernard
B
Patrone
Franco
F
Mostoslavsky
Raul
R
Uccelli
Antonio
A
Nencioni
Alessio
A
D000178:Acrylamides / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001343:Autophagy; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000737:chemistry*; D009243:NAD / Q000737:chemistry* / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000178:Acrylamides; D016207:Cytokines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D011065:Poly(ADP-ribose) Polymerases