The NAMPT–MMP-9 Axis Contributes to Chronic Inflammation in Cystic Fibrosis
6 affiliations
- 1Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy
- 2Department of Science and Technological Innovation, University of Eastern Piedmont, 15121 Alessandria, Italy
- 3Department of Clinical Sciences, Polytechnic University of Marche, 60126 Ancona, Italy
- 4Cystic Fibrosis Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
- 5Research Laboratories, Research and Innovation Department (DAIRI), IRCCS AOU SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy
- 6Department of Agriculture, Food and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
Abstract
Chronic inflammation is a major driver of lung damage in cystic fibrosis (CF), yet the molecular mechanisms that sustain this self-reinforcing inflammatory state remain incompletely understood. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis, can also act extracellularly (eNAMPT) as a pro-inflammatory mediator. Here, we investigated the relationship between NAMPT and matrix metalloproteinase-9 (MMP-9) in CF. Peripheral blood mononuclear cells (PBMCs) from people with CF (pwCF) displayed increased intracellular NAMPT and MMP-9 expression, together with enhanced AKT and ERK1/2 phosphorylation, compared with non-CF controls. Circulating eNAMPT levels were elevated in pwCF and positively correlated with MMP-9 levels. Although baseline eNAMPT levels were not significantly associated with FEV1% predicted, in a small longitudinal cohort, eNAMPT decreased following one year of elexacaftor/tezacaftor/ivacaftor (ETI) treatment, while FEV1% predicted increased in six of seven patients with paired measurements. In vitro, recombinant NAMPT increased MMP-9 expression and enzymatic activity in PBMCs from healthy donors. Pharmacological treatment with FK866 reduced endogenous eNAMPT release and attenuated NAMPT-induced MMP-9 production. Mechanistically, eNAMPT triggered rapid AKT activation followed by sustained ERK1/2 phosphorylation. Pharmacological inhibition of the MEK/ERK pathway attenuated NAMPT-induced MMP-9 activity, supporting a functional contribution of ERK1/2 signaling to NAMPT-mediated MMP-9 activation. Together, these findings identify a functional NAMPT–MMP-9 axis associated with inflammatory signaling in CF. Further studies are needed to establish its contribution to pulmonary inflammation and to determine the clinical significance of circulating eNAMPT in larger patient cohorts.
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BibTeX
@article{lori2026namptmmp9,
title = {{The NAMPT–MMP-9 Axis Contributes to Chronic Inflammation in Cystic Fibrosis}},
author = {Laura Lori and Irene Fiorilla and Beatrice Ghezzi and Marco Pedrazzi and Alberto Maria Todesco and Francesca Mazzola and Roberta De Tullio and Federico Cresta and Carlo Castellani and Mauro Patrone and Nadia Raffaelli and Valentina Audrito and Monica Averna},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219496},
url = {https://www.mdpi.com/1422-0067/27/21/9496},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The NAMPT–MMP-9 Axis Contributes to Chronic Inflammation in Cystic Fibrosis
AU - Laura Lori
AU - Irene Fiorilla
AU - Beatrice Ghezzi
AU - Marco Pedrazzi
AU - Alberto Maria Todesco
AU - Francesca Mazzola
AU - Roberta De Tullio
AU - Federico Cresta
AU - Carlo Castellani
AU - Mauro Patrone
AU - Nadia Raffaelli
AU - Valentina Audrito
AU - Monica Averna
PY - 2026
DA - 2026/10/24
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219496
UR - https://www.mdpi.com/1422-0067/27/21/9496
AB - Chronic inflammation is a major driver of lung damage in cystic fibrosis (CF), yet the molecular mechanisms that sustain this self-reinforcing inflammatory state remain incompletely understood. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis, can also act extracellularly (eNAMPT) as a pro-inflammatory mediator. Here, we investigated the relationship between NAMPT and matrix metalloproteinase-9 (MMP-9) in CF. Peripheral blood mononuclear cells (PBMCs) from people with CF (pwCF) displayed increased intracellular NAMPT and MMP-9 expression, together with enhanced AKT and ERK1/2 phosphorylation, compared with non-CF controls. Circulating eNAMPT levels were elevated in pwCF and positively correlated with MMP-9 levels. Although baseline eNAMPT levels were not significantly associated with FEV1% predicted, in a small longitudinal cohort, eNAMPT decreased following one year of elexacaftor/tezacaftor/ivacaftor (ETI) treatment, while FEV1% predicted increased in six of seven patients with paired measurements. In vitro, recombinant NAMPT increased MMP-9 expression and enzymatic activity in PBMCs from healthy donors. Pharmacological treatment with FK866 reduced endogenous eNAMPT release and attenuated NAMPT-induced MMP-9 production. Mechanistically, eNAMPT triggered rapid AKT activation followed by sustained ERK1/2 phosphorylation. Pharmacological inhibition of the MEK/ERK pathway attenuated NAMPT-induced MMP-9 activity, supporting a functional contribution of ERK1/2 signaling to NAMPT-mediated MMP-9 activation. Together, these findings identify a functional NAMPT–MMP-9 axis associated with inflammatory signaling in CF. Further studies are needed to establish its contribution to pulmonary inflammation and to determine the clinical significance of circulating eNAMPT in larger patient cohorts.
SN - 1422-0067
ER -