Abstract
Nicotinamide-phosphoribosyl transferase (NAMPT) constitutes the rate-limiting enzyme in the NAD salvage pathway that is essential for the maintenance of cellular NAD levels. Upon inflammation including inflammatory bowel diseases (IBD), NAMPT is strongly induced and thereby impedes an increased cellular NAD-wastage promoted by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD-metabolism. Here, we investigated the efficacy of NAMPT inhibition by the small-molecule inhibitor FK866 in models of acute colitis, colitis-associated cancer and on lamina propria mononuclear cells (LPMNC) from IBD patients. FK866 mitigated colitis and suppressed inflammation-associated tumorigenesis. NAMPT blockade resulted in NAD-depletion that was associated with reduced abundances and activities of PARP1, Sirt6 and CD38, decreased inflammatory monocytes, macrophages and activated T-cells. FK866-treatment effectively supressed cytokine production in human LPMNC and was further associated with an altered monocyte/macrophage biology, skewing macrophages towards an anti-inflammatory M2 phenotype. Our data suggest that targeting the NAD immunometabolism by FK866 constitutes a promising therapeutic approach in acute intestinal inflammation and colitis-associated tumorigenesis.
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