Abstract Background Nicotinamide phosphoribosyltransferase (NAMPT) is an essential and pleiotropic enzyme expressed in mammalian cells. Its intracellular form (iNAMPT) functions as the rate-limiting enzyme in the NAD+ salvage pathway. Through this activity, iNAMPT regulates cellular metabolism, mitochondrial biogenesis, and adaptive responses to inflammation and oxidative stress. In contrast, extracellular NAMPT (eNAMPT), secreted by multiple cell types including immune cells, acts as a pro-inflammatory cytokine and contributes to several inflammation-driven disorders such as inflammatory bowel disease (IBD). The mechanisms governing eNAMPT secretion and receptor engagement remain incompletely understood; to date, TLR4 is the only receptor that has been identified. Notably, circulating eNAMPT levels are elevated during active disease phases and negatively correlate with responsiveness to anti-TNF therapy (Colombo et al., 2020, 2022).We investigated the mechanistic contribution of eNAMPT to Crohn’s disease (CD) progression using the DNBS-induced colitis model. Methods BALB/c mice received intrarectal DNBS (2 mg for moderate or 3 mg for severe inflammation) and were treated daily with recombinant eNAMPT (50 µg/mouse) to mimic the elevated systemic levels observed in CD patients. Colon, blood, bone marrow were collected for flow cytometry, bulkRNAseq, array, RT-PCR and IHC. Results eNAMPT administration exacerbated disease severity, as evidenced by increased weight loss, colon shortening, and aggravated epithelial and mucosal damage on H however, its combination with IL-6 or G-CSF modestly enhanced colony formation, and a synergistic effect was observed with GM-CSF. Finally, the pathogenic activity of eNAMPT was abolished in TLR4-deficient mice, indicating a TLR4-dependent mechanism. Conclusion Collectively, these findings demonstrate that the cytokine eNAMPT exacerbates Crohn’s disease by acting along the gut–bone marrow axis, promoting HSC proliferation and differentiation toward immature granulocytes that infiltrate the colon and intensify fibrotic remodeling. References: Colombo G, Caviglia GP, Ravera A, Tribocco E, Frara S, Rosso C, Travelli C,Genazzani AA, Ribaldone DG. NAMPT and NAPRT serum levels predict response toanti-TNF therapy in inflammatory bowel disease. Front Med (Lausanne). 2023 Feb1;10:1116862. Colombo G, Clemente N, Zito A, Bracci C, Colombo FS, Sangaletti S, JachettiE, Ribaldone DG, Caviglia GP, Pastorelli L, De Andrea M, Naviglio S, Lucafò M,Stocco G, Grolla AA, Campolo M, Casili G, Cuzzocrea S, Esposito E, Malavasi F,Genazzani AA, Porta C, Travelli C. Neutralization of extracellular NAMPT(nicotinamide phosphoribosyltransferase) ameliorates experimental murinecolitis. J Mol Med (Berl). 2020 Apr;98(4):595-612. Sezaki M, Hayashi Y, Nakato G, Wang Y, Nakata S, Biswas S, Morishima T,Fakruddin M, Moon J, Ahn S, Kim P, Miyamoto Y, Baba H, Fukuda S, Takizawa H.Hematopoietic stem and progenitor cells integrate microbial signals to promotepost-inflammation gut tissue repair. EMBO J. 2022 Nov 17;41(22):e110712. Conflict of interest: Travelli, Cristina: No conflict of interest Cascetta, Greta: No conflict of interest Eremita, Gianmarco: No conflict of interest Balestrero, Federica Carolina: No conflict of interest Meggiolan, Aurora: No conflict of interest Bello, Ivana: No conflict of interest Ferramosca, Angela: No conflict of interest Caputo, Emanuela: No conflict of interest Grimaldi, Riccardo Maria: No conflict of interest Porta, Chiara: No conflict of interest Panza, Elisabetta: No conflict of interest Matteoli, Ginaluca: No conflict of interest Racchi, Marco: No conflict of interest Sangaletti, Sabina: No conflict of interest Colombo, Giorgia: No conflict of interest
Travelli et al. (Thu,) studied this question.