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Mucosal immunity
Original article
NAD metabolism fuels human and mouse intestinal inflammation
  1. Romana R Gerner1,2,
  2. Victoria Klepsch3,
  3. Sophie Macheiner1,2,
  4. Kathrin Arnhard4,
  5. Timon E Adolph1,
  6. Christoph Grander1,
  7. Verena Wieser1,
  8. Alexandra Pfister1,2,
  9. Patrizia Moser5,
  10. Natascha Hermann-Kleiter3,
  11. Gottfried Baier,
  12. Herbert Oberacher4,
  13. Herbert Tilg1,
  14. Alexander R Moschen1,2
  1. 1 Division of Internal Medicine I, Department of Medicine, Medical University Innsbruck, Innsbruck, Austria
  2. 2 Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria
  3. 3 Division of Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University Innsbruck, Innsbruck, Austria
  4. 4 Institute of Legal Medicine and Core Facility Metabolomics, Medical University Innsbruck, Innsbruck, Austria
  5. 5 Department of Pathology, Medical University Innsbruck, Innsbruck, Austria
  1. Correspondence to Dr Romana R Gerner and Dr Alexander R Moschen, Christian Doppler Laboratory for Mucosal Immunology, Peter-Mayr-Str 1, A-6020 Innsbruck, Austria; Romana.Gerner{at}i-med.ac.at, alexander.moschen{at}i-med.ac.at

Abstract

Objective Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism.

Design We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.

Results FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1−⁄− mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10.

Conclusion Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

  • Energy Metabolism
  • Colonic Mucosal Metabolism
  • Gut Inflammation
  • IBD Basic Research
  • Inflammatory Bowel Disease

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2017-314241

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    Footnotes

    • Contributors Conceptualisation: RRG, HT, ARM. Experimental procedures: RRG, VK, SM, CG. Statistical analysis: RRG, VK. Investigation: RRG, VK, KA, VW, AP, NHK. Resources, materials and technical support: AP, PM, GB, HO. Figure preparation: RRG, VK, ARM. Writing of original draft: RRG, TEA, HT, ARM. Writing of revised draft: RRG, TEA, HT, ARM. Funding acquisition: HT, ARM.

    • Funding This study was supported by the Tyrolean Research Foundation (TWF-0404/1480 to ARM) and the Christian Doppler Research Foundation. The financial support by the Austrian Federal Ministry of Science, Research and Economy and the National Foundation for Research, Technology and Development is gratefully acknowledged. HT is supported by the excellence initiative (Competence Centers for Excellent Technologies—COMET) of the Austrian Research Promotion Agency FFG: Research Center of Excellencein Vascular Ageing Tyrol, VASCage (K-Project No. 843536) funded by the BMVIT, BMWFW, the Wirtschaftsagentur Wien and the Standortagentur Tirol.

    • Competing interests None declared.

    • Patient consent Parental/guardian consent obtained.

    • Ethics approval Institutional Ethics Committee (AN2015-0132 to HT)

    • Provenance and peer review Not commissioned; externally peer reviewed.