Extracellular nicotinate phosphoribosyltransferasebinds Toll like receptor 4 and mediatesinflammation

Damage-associated molecular patterns (DAMPs) are molecules that can be actively orpassively released by injured tissues and that activate the immune system. Here we showthat nicotinate phosphoribosyltransferase (NAPRT), detected by antibody-mediated assaysand mass spectrometry, is an extracellular ligand for Toll-like receptor 4 (TLR4) and a criticalmediator of inflammation, acting as a DAMP. Exposure of human and mouse macrophages toNAPRT activates the inflammasome and NF-κB for secretion of inflammatory cytokines.Furthermore, NAPRT enhances monocyte differentiation into macrophages by inducingmacrophage colony-stimulating factor. These NAPRT-induced effects are independent ofNAD-biosynthetic activity, but rely on NAPRT binding to TLR4. In line with ourfinding thatNAPRT mediates endotoxin tolerance in vitro and in vivo, sera from patients with sepsiscontain the highest levels of NAPRT, compared to patients with other chronic inflammatoryconditions. Together, these data identify NAPRT as a endogenous ligand for TLR4 and amediator of inflammation.