Pro-inflammatory role of extracellular nicotinamide phosphoribosyltransferase in cystic fibrosis

The introduction of the triple combination of CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor (ETI) has improved cystic fibrosis (CF) care, however its impact on CF airway epithelial cell inflammation requires further investigation. Previous studies have shown elevated Matrix Metalloproteinase 9 (MMP9) plasma levels in CF patients compared to healthy subjects. Notably, in patients responding positively to ETI, MMP9 levels significantly decreased, whereas non- responders showed no variation. Stress and inflammation are known to drive immune cells to release extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) which acts as pro-inflammatory cytokine. This suggests a potential link between MMP9 modulation and eNAMPT activity. Our aim is to investigate this relationship to obtain a deeper understanding of the mechanisms underlying persistent chronic respiratory inflammation and identify new potential anti-inflammatory therapeutic targets in CF. ELISA analysis showed significantly higher plasmatic eNAMPT levels in CF patients (n=12) compared to non-CF controls (n=18). Moreover, the immunoblotting analysis performed on healthy PBMCs treated for 24 hours with a recombinant NAMPT revealed a significant increase in MMP9 expression compared to the untreated condition. Consistently, zymography analysis confirmed enhanced MMP9 activity in the supernatants of treated PBMCs. Intracellular signaling analysis performed on PBMCs collected from the same experiments suggested an involvement of ERK1/2/NFkB pathway in eNAMPT-induced MMP9 production. This study proposes, for the first time, a correlation among eNAMPT, MMP9 and CF, offering new insights into the mechanisms underlying chronic inflammation identifying NAMPT as a potential modulator of MMP-9 activity and a possible novel therapeutic target for reducing inflammation in CF patients.