Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation

Damage-associated molecular patterns (DAMPs) are molecules that can be actively or passively released by injured tissues and that activate the immune system. Here we show that nicotinate phosphoribosyltransferase (NAPRT), detected by antibody-mediated assays and mass spectrometry, is an extracellular ligand for Toll-like receptor 4 (TLR4) and a critical mediator of inflammation, acting as a DAMP. Exposure of human and mouse macrophages to NAPRT activates the inflammasome and NF-κB for secretion of inflammatory cytokines. Furthermore, NAPRT enhances monocyte differentiation into macrophages by inducing macrophage colony-stimulating factor. These NAPRT-induced effects are independent of NAD-biosynthetic activity, but rely on NAPRT binding to TLR4. In line with our finding that NAPRT mediates endotoxin tolerance in vitro and in vivo, sera from patients with sepsis contain the highest levels of NAPRT, compared to patients with other chronic inflammatory conditions. Together, these data identify NAPRT as a endogenous ligand for TLR4 and a mediator of inflammation.

Publication year: 2019
Authors: Antonella Managò1,12, Valentina Audrito1,12, Francesca Mazzola2, Leonardo Sorci 3, Federica Gaudino1, Katiuscia Gizzi4, Nicoletta Vitale5, Danny Incarnato6, Gabriele Minazzato7, Alice Ianniello8, Antonio Varriale9, Sabato D’Auria9, Giulio Mengozzi8, Gianfranco Politano 10, Salvatore Oliviero 4,11, Nadia Raffaelli7,13 & Silvia Deaglio 1,13

1 Department of Medical Sciences, University of Turin, Turin, Italy.

2 Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy.

3 Department of Materials, Environmental Sciences and Urban Planning, Division of Bioinformatics and Biochemistry, Polytechnic University of Marche, Ancona, Italy.

4 Italian Institute for Genomic Medicine, Turin, Italy.

5 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin,

6 Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, The Netherlands.

7 Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy.

8 Department of Laboratory Medicine, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Turin, Italy.

9 Institute of Food Science, CNR, Avellino, Italy.

10 Department of Control and Computer Engineering, Polytechnic University of Turin, Turin, Italy.

11 Department of Life Sciences and Systems Biology, University of Turin, Turin,Italy.

These authors contributed equally: Antonella Managò, Valentina Audrito.

These authors jointly supervised: Nadia Raffaelli, Silvia Deaglio.

Published in: Nature communications
DOI: doi.org/10.1038/s41467-019-12055-2


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