Targeting Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic idiopathic disorder. Although biologics have increased the probability to maintain remission of the disease, a considerable percentage of patients still do not respond to therapies. Therefore, there is an unmet medical need for novel targeted therapies to control these diseases. In this setting, Nicotinamide phosphoribosyltrasferase (NAMPT), a pleiotropic enzyme involved in cellular metabolism, has been hypothesized as a novel target. NAMPT is present in two different forms: an intracellular form, called iNAMPT, involved in NAD synthesis, and an extracellular form, eNAMPT that acts as cytokine on different cell types (i.e., immune cells), binding to a still unknown receptor. Importantly, ENAMPT levels are increased in IBD and its levels correlate with the stage of the pathology: in an active state of the disease its levels are extremely high, however they are partially reduced in a remission stage. Exogenous administration of eNAMPT in DNBS model determined a worsening of IBD symptoms (increased weight loss, colon shortening and tissue damage). These symptoms are reduced after the treatment with a novel anti-eNAMPT antibody (C269), observable in a reduction in IBD symptoms and a reduction in mRNA proinflammatory IFNy-associated genes, usually upregulated in IBD. Moreover, C269 reduced the frequency of myeloid and T cells in lamina propria. Ex vivo data on murine macrophages reveals that eNAMPT has pro-inflammatory and pro migratory activity. We have demonstrated that ENAMPT priming of PECS enhances IFNy dependent response, through STAT and NF-kB-dependent mechanism, reverted with C269 pre treatment. Furthermore, eNAMPT also induced macrophage migration, in the same manner of LPS. Taken together, our data demonstrated that ENAMPT exacerbates DNBS-associated symptoms, in which its neutralization could ameliorate the pathogenesis of the disease, focusing on macrophages plasticity as a possible target