NAD metabolism fuels human and mouse intestinal inflammation

Romana R Gerner, Victoria Klepsch, Sophie Macheiner, Kathrin Arnhard, Timon E Adolph, Christoph Grander, Verena Wieser, Alexandra Pfister, Patrizia Moser, Natascha Hermann-Kleiter, Gottfried Baier, Herbert Oberacher, Herbert Tilg, Alexander R Moschen, Romana R Gerner, Victoria Klepsch, Sophie Macheiner, Kathrin Arnhard, Timon E Adolph, Christoph Grander, Verena Wieser, Alexandra Pfister, Patrizia Moser, Natascha Hermann-Kleiter, Gottfried Baier, Herbert Oberacher, Herbert Tilg, Alexander R Moschen

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.

Keywords: Colonic Mucosal Metabolism; Energy Metabolism; Gut Inflammation; IBD Basic Research; Inflammatory Bowel Disease.

Conflict of interest statement

Competing interests: None declared.

© 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.

Figures

Figure 1
Figure 1
FK866 treatment mitigates clinical, morphological and biochemical parameters of DSS colitis. (A) Colonic Nampt mRNA induction as determined by RT-qPCR (black labelling) is shown together with the weight course (grey symbols and labelling) and NAMPT protein expression using immunoblot analyses along with densitometric quantification during DSS colitis. (B) Comparative NAMPT immunohistochemistry of colons with or without DSS on day 9 of experiments is shown (left panel). NAMPT positivity (red) is observed in IEC and inflammatory cells (15× magnification; scale bars 100 µm). Colonic NAMPT expression of Epcam+epithelial cells and CD45+LPMNC including respective immune cell subsets was analysed by flow cytometry in the steady state and on day 7 of colitis (pie charts). (C) Weight course of vehicle control and FK866-treated mice during DSS colitis. The experimental outline is shown above. (D) Mean colon lengths and faecal Lcn2 of respective groups are shown. (E) Representative H&E stainings of colons along with histological severity scores (5× magnification; scale bars 500 µm). (F) mRNA expression of cytokines and chemokines of mucosal scrapings was determined by RT-qPCR and normalised to ß-actin (day 7 of experiments). n=6–10 per group, five independent experiments. Data represent mean±SEM. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; Student’s t-test or one-way analysis of variance followed by Bonferroni’s post hoc corrections when more than three groups analysed. CCL, CC-chemokine ligand; CXCL, C-X-C motif ligand; DSS, dextran sulfate sodium; IEC, intestinal epithelial cells; IL, interleukin; IP, induced protein; Lcn2, lipocalin 2; LPMNC, lamina propria mononuclear cells; Mip, macrophage inflammatory protein; NAMPT, nicotinamide phosphoribosyltransferase; RLU, relative light units; TNFα, tumour necrosis factor alpha.
Figure 2
Figure 2
FK866 treatment is effective independent of T and B cells. (A) Weight course of vehicle control and FK866-treated RAG−/− mice during DSS colitis along with the experimental outline shown above. (B) Representative H&E-stained colonic sections along with histology score of indicated groups (5× magnification; scale bars 500 µm). (C,D) Mean colon lengths and (D) faecal Lcn2 of experimental groups are shown. (E) Colonic scrapings were analysed for mRNA expression of respective cytokines/chemokines on experimental day 7 with or without DSS. n=10 per group, two independent experiments. Data represent mean±SEM. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; Student’s t-test or one-way analysis of variance followed by Bonferroni’s post hoc corrections when more than three groups analysed. CCL, CC-chemokine ligand; CXCL, C-X-C motif ligand; DSS, dextran sulfate sodium; IL, interleukin; IP, induced protein; Lcn2, lipocalin 2; Mip, macrophage inflammatory protein; TNFα, tumour necrosis factor alpha.
Figure 3
Figure 3
NAMPT blockage results in a diminished recruitment of inflammatory/activated cells upon intestinal inflammation. (A) Total numbers of colonic infiltrates were quantified by automated cell counting (left). The absolute numbers of CD11b+F4/80hi tissue macrophages, CD11c+MHC-II+-activated dendritic cells, CD11b+Ly6Cloresident monocytes and CD11b+Ly6Chi inflammatory monocytes per colon with or without FK866 during tap water or DSS colitis were analysed by flow cytometry on day 7. (B) On day 7 of colitis, the absolute numbers of CD19+ B cells, CD3+, CD4+ and CD4+CD38+, and CD8+ and CD8+CD38+ T cells per colon of respective groups were analysed by flow cytometry. (C) The mRNA expression of common adhesion molecules was determined by RT-qPCR in mucosal scrapings (n=6–8, two independent experiments). (D) The frequency of Sca1+ stem cell-like cells, CD11b+Ly6Chi inflammatory and CD11b+Ly6Clo resident monocytes of CD45+-gated BM cells was analysed by flow cytometry (n=4–6, two independent experiments). n=4–8 per group, six independent experiments if not otherwise stated. Data represent mean±SEM. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; one-way analysis of variance followed by Bonferroni’s post hoc corrections when more than three groups analysed. BM, bone marrow; DSS, dextran sulfate sodium; LPMNC, lamina propria mononuclear cells; NAMPT, nicotinamide phosphoribosyltransferase.
Figure 5
Figure 5
FK866-treated mice are protected in the AOM/DSS model of colitis-associated cancer. (A) The experimental outline along with the weight course is shown. (B,C) Clinical parameters including (B) survival and (C) mean colon lengths of FK866 compared with vehicle-treated mice during the AOM/DSS model. (D) Cell death was evaluated by the TUNEL method. Three crypts/mouse were analysed for TUNEL+cells and expressed as ratio/total IEC count on the crypt axis. (E) The mean tumour numbers and tumour areas of FK866 or vehicle-treated animals were assessed in H&E-stained Swiss roll sections. Dashed, black lines indicate tumour area (5× magnification; scale bars 500 µm). n=12 per group, two independent experiments. Data represent mean±SEM. *p

Figure 6

Therapeutic FK866 treatment is effective…

Figure 6

Therapeutic FK866 treatment is effective on established colitis and modulates proinflammatory cytokine secretion…

Figure 6
Therapeutic FK866 treatment is effective on established colitis and modulates proinflammatory cytokine secretion in human LPMNC from patients with IBD. (A) Histological severity score of mice treated with DSS at 0, 1 and 3 days. (B) FK866 or vehicle treatment was started 3 days after onset of DSS experiments and animals were assessed for clinical parameters including (B) weight loss, (C) colon length and faecal Lcn2 on experimental day 9. (D) Representative H&E-stained colons and respective colitis scores of indicated groups are depicted. (5× magnification; scale bars 500 µm). (E) A schematic flow chart of LPMNC experiments is outlined. (F) Biopsy-derived LPMNCs from patients with CD (upper panel) or UC (lower panel) were incubated with or without infliximab (10 µg/mL), dexamethasone (2 nM) or FK866 (200 nM) and assayed for cytokine release after 18 hours. Vehicle-stimulated cells were set as 100% and data are expressed as % decrease or increase (n=8–10 per group). n=8 per group if not otherwise stated, two independent experiments. Data represent mean±SEM. *p

Figure 4

FK866-induced NAD depletion results in…

Figure 4

FK866-induced NAD depletion results in reduced PARP1 and Sirt6 activity and skews macrophages…

Figure 4
FK866-induced NAD depletion results in reduced PARP1 and Sirt6 activity and skews macrophages towards a less inflammatory phenotype. (A) An experimental outline of the LC-MS/MS approach is shown. Mucosal metabolite concentrations of the NAD salvage pathway along with ATP concentrations of indicated groups during tap water or DSS exposure were determined and normalised to total protein contents. (B,C) Representative PARP1 and Sirt6 immunoblots from mucosal scrapings of indicated groups along with densitometry, and (C) poly(ADP-ribosylation) (PAR) assay or sirtuin deacetylase activity (DAA). (D) Comparative PARP1 and Sirt6 immunohistochemistry of colons with or without FK866 during tap water or DSS exposure on day 7 of experiments is shown (20× magnification; scale bars 50 µm). (E) BMDMs were differentiated for 8 days followed by polarisation with M1 (LPS/IFNγ) or M2 (IL-4) stimuli for 24 hours. Cells were incubated with or without (=ctr) 5 nM FK866 from day 0 (=FK866_d0) or from day 8 (=FK866_d8). On day 9, cell viability was assessed by a LUNA automated cell counter and cells analysed for typical M1 (MHC-II, CD86) and M2 (CD206) surface markers by flow cytometry. n=2–4 per group. mRNA expression of typical M1 (Socs3, Nos2) and M2 (IL-10, Arg1) markers was analysed by quantitative RT-PCR and normalised to HPRT and SNs were assayed for IL-6 and IL-10 by ELISA on day 9. (F) The M1/M2 ratio in the colon of mice with or without FK866 in the steady state and during DSS colitis on day 7 is shown. The frequencies of colonic F4/80+ CD38+-M1 macrophages of FK866 or vehicle-treated mice are depicted in the overlays. n=2–8 per group if not otherwise stated, three independent experiments. Data represent mean±SEM. *p<0.05; **p<0.01; ***p<0.001; Student’s t-test or one-way analysis of variance followed by Bonferroni’s post hoc corrections when more than three groups analysed. BMDM, bone marrow-derived macrophages; DSS, dextran sulfate sodium; HPRT, hypoxanthine-guanine phosphoribosyltransferase; IFNγ, interferon gamma; IL, interleukin; LC-MS/MS, liquid chromatography tandem-mass spectrometry; LPS, lipopolysaccharide; MHC, major histocompatibility complex; NAD, nicotinamide adenine; dinucleotide; NMN, nicotinamide mononucleotide; PAR, poly(ADP-ribose); PARP, poly(ADP-ribose) polymerase; RLU, relative light units; SN, supernatant.
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References
    1. Kaser A, Zeissig S, Blumberg RS, et al. . Inflammatory bowel disease. Annu Rev Immunol 2010;28:573–621. 10.1146/annurev-immunol-030409-101225 - DOI - PMC - PubMed
    1. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48:526–35. 10.1136/gut.48.4.526 - DOI - PMC - PubMed
    1. Dignass A, Lindsay JO, Sturm A, et al. . Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012;6:991–1030. 10.1016/j.crohns.2012.09.002 - DOI - PubMed
    1. Dignass A, Van Assche G, Lindsay JO, et al. . The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Current management. J Crohns Colitis 2010;4:28–62. 10.1016/j.crohns.2009.12.002 - DOI - PubMed
    1. Feagan BG, Sandborn WJ, Gasink C, et al. . Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med 2016;375:1946–60. 10.1056/NEJMoa1602773 - DOI - PubMed
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Figure 6
Figure 6
Therapeutic FK866 treatment is effective on established colitis and modulates proinflammatory cytokine secretion in human LPMNC from patients with IBD. (A) Histological severity score of mice treated with DSS at 0, 1 and 3 days. (B) FK866 or vehicle treatment was started 3 days after onset of DSS experiments and animals were assessed for clinical parameters including (B) weight loss, (C) colon length and faecal Lcn2 on experimental day 9. (D) Representative H&E-stained colons and respective colitis scores of indicated groups are depicted. (5× magnification; scale bars 500 µm). (E) A schematic flow chart of LPMNC experiments is outlined. (F) Biopsy-derived LPMNCs from patients with CD (upper panel) or UC (lower panel) were incubated with or without infliximab (10 µg/mL), dexamethasone (2 nM) or FK866 (200 nM) and assayed for cytokine release after 18 hours. Vehicle-stimulated cells were set as 100% and data are expressed as % decrease or increase (n=8–10 per group). n=8 per group if not otherwise stated, two independent experiments. Data represent mean±SEM. *p

Figure 4

FK866-induced NAD depletion results in…

Figure 4

FK866-induced NAD depletion results in reduced PARP1 and Sirt6 activity and skews macrophages…

Figure 4
FK866-induced NAD depletion results in reduced PARP1 and Sirt6 activity and skews macrophages towards a less inflammatory phenotype. (A) An experimental outline of the LC-MS/MS approach is shown. Mucosal metabolite concentrations of the NAD salvage pathway along with ATP concentrations of indicated groups during tap water or DSS exposure were determined and normalised to total protein contents. (B,C) Representative PARP1 and Sirt6 immunoblots from mucosal scrapings of indicated groups along with densitometry, and (C) poly(ADP-ribosylation) (PAR) assay or sirtuin deacetylase activity (DAA). (D) Comparative PARP1 and Sirt6 immunohistochemistry of colons with or without FK866 during tap water or DSS exposure on day 7 of experiments is shown (20× magnification; scale bars 50 µm). (E) BMDMs were differentiated for 8 days followed by polarisation with M1 (LPS/IFNγ) or M2 (IL-4) stimuli for 24 hours. Cells were incubated with or without (=ctr) 5 nM FK866 from day 0 (=FK866_d0) or from day 8 (=FK866_d8). On day 9, cell viability was assessed by a LUNA automated cell counter and cells analysed for typical M1 (MHC-II, CD86) and M2 (CD206) surface markers by flow cytometry. n=2–4 per group. mRNA expression of typical M1 (Socs3, Nos2) and M2 (IL-10, Arg1) markers was analysed by quantitative RT-PCR and normalised to HPRT and SNs were assayed for IL-6 and IL-10 by ELISA on day 9. (F) The M1/M2 ratio in the colon of mice with or without FK866 in the steady state and during DSS colitis on day 7 is shown. The frequencies of colonic F4/80+ CD38+-M1 macrophages of FK866 or vehicle-treated mice are depicted in the overlays. n=2–8 per group if not otherwise stated, three independent experiments. Data represent mean±SEM. *p<0.05; **p<0.01; ***p<0.001; Student’s t-test or one-way analysis of variance followed by Bonferroni’s post hoc corrections when more than three groups analysed. BMDM, bone marrow-derived macrophages; DSS, dextran sulfate sodium; HPRT, hypoxanthine-guanine phosphoribosyltransferase; IFNγ, interferon gamma; IL, interleukin; LC-MS/MS, liquid chromatography tandem-mass spectrometry; LPS, lipopolysaccharide; MHC, major histocompatibility complex; NAD, nicotinamide adenine; dinucleotide; NMN, nicotinamide mononucleotide; PAR, poly(ADP-ribose); PARP, poly(ADP-ribose) polymerase; RLU, relative light units; SN, supernatant.
Figure 4
Figure 4
FK866-induced NAD depletion results in reduced PARP1 and Sirt6 activity and skews macrophages towards a less inflammatory phenotype. (A) An experimental outline of the LC-MS/MS approach is shown. Mucosal metabolite concentrations of the NAD salvage pathway along with ATP concentrations of indicated groups during tap water or DSS exposure were determined and normalised to total protein contents. (B,C) Representative PARP1 and Sirt6 immunoblots from mucosal scrapings of indicated groups along with densitometry, and (C) poly(ADP-ribosylation) (PAR) assay or sirtuin deacetylase activity (DAA). (D) Comparative PARP1 and Sirt6 immunohistochemistry of colons with or without FK866 during tap water or DSS exposure on day 7 of experiments is shown (20× magnification; scale bars 50 µm). (E) BMDMs were differentiated for 8 days followed by polarisation with M1 (LPS/IFNγ) or M2 (IL-4) stimuli for 24 hours. Cells were incubated with or without (=ctr) 5 nM FK866 from day 0 (=FK866_d0) or from day 8 (=FK866_d8). On day 9, cell viability was assessed by a LUNA automated cell counter and cells analysed for typical M1 (MHC-II, CD86) and M2 (CD206) surface markers by flow cytometry. n=2–4 per group. mRNA expression of typical M1 (Socs3, Nos2) and M2 (IL-10, Arg1) markers was analysed by quantitative RT-PCR and normalised to HPRT and SNs were assayed for IL-6 and IL-10 by ELISA on day 9. (F) The M1/M2 ratio in the colon of mice with or without FK866 in the steady state and during DSS colitis on day 7 is shown. The frequencies of colonic F4/80+ CD38+-M1 macrophages of FK866 or vehicle-treated mice are depicted in the overlays. n=2–8 per group if not otherwise stated, three independent experiments. Data represent mean±SEM. *p<0.05; **p<0.01; ***p<0.001; Student’s t-test or one-way analysis of variance followed by Bonferroni’s post hoc corrections when more than three groups analysed. BMDM, bone marrow-derived macrophages; DSS, dextran sulfate sodium; HPRT, hypoxanthine-guanine phosphoribosyltransferase; IFNγ, interferon gamma; IL, interleukin; LC-MS/MS, liquid chromatography tandem-mass spectrometry; LPS, lipopolysaccharide; MHC, major histocompatibility complex; NAD, nicotinamide adenine; dinucleotide; NMN, nicotinamide mononucleotide; PAR, poly(ADP-ribose); PARP, poly(ADP-ribose) polymerase; RLU, relative light units; SN, supernatant.

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