Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation

Antonella Managò, Valentina Audrito, Francesca Mazzola, Leonardo Sorci, Federica Gaudino, Katiuscia Gizzi, Nicoletta Vitale, Danny Incarnato, Gabriele Minazzato, Alice Ianniello, Antonio Varriale, Sabato D’Auria, Giulio Mengozzi, Gianfranco Politano, Salvatore Oliviero, Nadia Raffaelli and Silvia Deaglio ()
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Antonella Managò: University of Turin
Valentina Audrito: University of Turin
Francesca Mazzola: Polytechnic University of Marche
Leonardo Sorci: Polytechnic University of Marche
Federica Gaudino: University of Turin
Katiuscia Gizzi: Italian Institute for Genomic Medicine
Nicoletta Vitale: University of Turin
Danny Incarnato: University of Groningen
Gabriele Minazzato: Polytechnic University of Marche
Alice Ianniello: Azienda Ospedaliero-Universitaria Città della Salute e della Scienza
Antonio Varriale: Institute of Food Science, CNR
Sabato D’Auria: Institute of Food Science, CNR
Giulio Mengozzi: Azienda Ospedaliero-Universitaria Città della Salute e della Scienza
Gianfranco Politano: Polytechnic University of Turin
Salvatore Oliviero: Italian Institute for Genomic Medicine
Nadia Raffaelli: Polytechnic University of Marche
Silvia Deaglio: University of Turin

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12055-2

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