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; Silvia Deaglio

doi:10.1038/s41467-019-12055-2

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, Silvia Deaglio^*

^*Corresponding author for this work

Molecular Genetics

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	4116
Number of pages	14
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12055-2
Publication status	Published - 11-Sept-2019

Keywords

COLONY-STIMULATING FACTOR
ACID PHOSPHYRIBOSYLTRANSFERASE
NAMPT INHIBITORS
ENHANCING FACTOR
CELL PHYSIOLOGY
EXPRESSION
METABOLISM
SEQUENCE
NAD(+)
POLARIZATION

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Extracellular nicotinate phosphoribosyltransferase binds TollFinal publisher's version, 3.3 MBLicence: CC BY

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Managò, A., Audrito, V., Mazzola, F., Sorci, L., Gaudino, F., Gizzi, K., Vitale, N., Incarnato, D., Minazzato, G., Ianniello, A., Varriale, A., D'Auria, S., Mengozzi, G., Politano, G., Oliviero, S., Raffaelli, N., & Deaglio, S. (2019). Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation. Nature Communications, 10(1), Article 4116. https://doi.org/10.1038/s41467-019-12055-2

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title = "Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation",

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.",

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author = "Antonella Manag{\`o} and Valentina Audrito and Francesca Mazzola and Leonardo Sorci and Federica Gaudino and Katiuscia Gizzi and Nicoletta Vitale and Danny Incarnato and Gabriele Minazzato and Alice Ianniello and Antonio Varriale and Sabato D'Auria and Giulio Mengozzi and Gianfranco Politano and Salvatore Oliviero and Nadia Raffaelli and Silvia Deaglio",

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Managò, A, Audrito, V, Mazzola, F, Sorci, L, Gaudino, F, Gizzi, K, Vitale, N, Incarnato, D, Minazzato, G, Ianniello, A, Varriale, A, D'Auria, S, Mengozzi, G, Politano, G, Oliviero, S, Raffaelli, N & Deaglio, S 2019, 'Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation', Nature Communications, vol. 10, no. 1, 4116. https://doi.org/10.1038/s41467-019-12055-2

TY - JOUR

T1 - Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation

AU - Managò, Antonella

AU - Audrito, Valentina

AU - Mazzola, Francesca

AU - Sorci, Leonardo

AU - Gaudino, Federica

AU - Gizzi, Katiuscia

AU - Vitale, Nicoletta

AU - Incarnato, Danny

AU - Minazzato, Gabriele

AU - Ianniello, Alice

AU - Varriale, Antonio

AU - D'Auria, Sabato

AU - Mengozzi, Giulio

AU - Politano, Gianfranco

AU - Oliviero, Salvatore

AU - Raffaelli, Nadia

AU - Deaglio, Silvia

PY - 2019/9/11

Y1 - 2019/9/11

N2 - 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.

AB - 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.

KW - COLONY-STIMULATING FACTOR

KW - ACID PHOSPHYRIBOSYLTRANSFERASE

KW - NAMPT INHIBITORS

KW - ENHANCING FACTOR

KW - CELL PHYSIOLOGY

KW - EXPRESSION

KW - METABOLISM

KW - SEQUENCE

KW - NAD(+)

KW - POLARIZATION

U2 - 10.1038/s41467-019-12055-2

DO - 10.1038/s41467-019-12055-2

M3 - Article

C2 - 31511522

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4116

ER -

Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation

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Keywords

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