TY - JOUR
T1 - NAD metabolism fuels human and mouse intestinal inflammation
AU - Gerner, Romana R.
AU - Klepsch, Victoria
AU - Macheiner, Sophie
AU - Arnhard, Kathrin
AU - Adolph, Timon E.
AU - Grander, Christoph
AU - Wieser, Verena
AU - Pfister, Alexandra
AU - Moser, Patrizia
AU - Hermann-Kleiter, Natascha
AU - Baier, Gottfried
AU - Oberacher, Herbert
AU - Tilg, Herbert
AU - Moschen, Alexander R.
N1 - Publisher Copyright:
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042566641&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2017-314241
DO - 10.1136/gutjnl-2017-314241
M3 - Article
C2 - 28877980
AN - SCOPUS:85042566641
SN - 0017-5749
VL - 67
SP - 1813
EP - 1823
JO - Gut
JF - Gut
IS - 10
ER -
