Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE

Santina Bruzzone, Floriana Fruscione, Sara Morando, Tiziana Ferrando, Alessandro Poggi, Anna Garuti, Agustina D'Urso, Martina Selmo, Federica Benvenuto, Michele Cea, Gabriele Zoppoli, Eva Moran, Debora Soncini, Alberto Ballestrero, Bernard Sordat, Franco Patrone, Raul Mostoslavsky, Antonio Uccelli, Alessio Nencioni

Research output: Contribution to journalArticle

Abstract

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-γ and TNF-α 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-γ and TNF-α 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.

Original languageEnglish
Article numbere7897
JournalPLoS One
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 19 2009

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Bruzzone, S., Fruscione, F., Morando, S., Ferrando, T., Poggi, A., Garuti, A., D'Urso, A., Selmo, M., Benvenuto, F., Cea, M., Zoppoli, G., Moran, E., Soncini, D., Ballestrero, A., Sordat, B., Patrone, F., Mostoslavsky, R., Uccelli, A., & Nencioni, A. (2009). Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. PLoS One, 4(11), [e7897]. https://doi.org/10.1371/journal.pone.0007897