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Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation

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., 11-Sep-2019, In : Nature Communications. 10, 1, 14 p., 4116.

Research output: Contribution to journalArticleAcademicpeer-review

  • 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

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 languageEnglish
Article number4116
Number of pages14
JournalNature Communications
Volume10
Issue number1
Publication statusPublished - 11-Sep-2019

    Keywords

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

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