Nicotinamide phosphoribosyl
transferase (NAMPT) is required to maintain the NAD+ pool, among which extracellular (e) NAMPT is associated with
inflammation, mainly mediated by macrophages. However, the role of (e) NAMPT in inflammatory macrophages in
ulcerative colitis is insufficiently understood. Here our analyses of single-cell
RNA-seq data revealed that the levels of NAMPT and CYBB/NOX2 in macrophages were elevated in patients with
colitis and in mouse models of acute and chronic
colitis. These findings indicate the clinical significance of NAMPT and CYBB in
colitis. Further, we found that eNAMPT directly binds the extracellular domains of CYBB and TLR4 in activated NLRP3
inflammasomes. Moreover, we developed a recombinant 12-residue TK
peptide designated colon-targeted (CT)-conjugated multifunctional NAMPT (rCT-NAMPT), comprising CT as the colon-targeting moiety, which harbors the minimal essential residues required for CYBB/TLR4 binding. rCT-NAMPT effectively suppressed the severity of disease in DSS-induced acute and chronic
colitis models through targeting the colon and inhibiting the interaction of NAMPT with CYBB or TLR4. Together, our data show that rCT-NAMPT may serve as an effective novel candidate therapeutic for
colitis by modulating the NLRP3
inflammasome-mediated immune signaling system.