Extracellular Poly(ADP-Ribose) Is a Pro-inflammatory Signal for Macrophages

Poly(ADP-ribose) polymerase 1 (PARP1) synthesizes poly(ADP-ribose) (PAR), an essential post-translational modification whose function is important in many cellular processes including DNA damage signaling, cell death, and inflammation. All known PAR biology is intracellular, but we suspected it might also play a role in cell-to-cell communication during inflammation. We found that PAR activated cytokine release in human and mouse macrophages, a hallmark of innate immune activation, and determined structure-activity relationships. PAR was rapidly internalized by murine macrophages, while the monomer, ADP-ribose, was not. Inhibitors of Toll-like receptor 2 (TLR2) and TLR4 signaling blocked macrophage responses to PAR, and PAR induced TLR2 and TLR4 signaling in reporter cell lines suggesting it was recognized by these TLRs, much like bacterial pathogens. We propose that PAR acts as an extracellular damage associated molecular pattern that drives inflammatory signaling. [Display omitted] •Poly(ADP-ribose) stimulates cytokine secretion in human and mouse macrophages•Poly(ADP-ribose) activates phagocytosis in mouse macrophages•A dimer of poly(ADP-ribose) is sufficient for macrophage activation•TLR2 and TLR4 mediate poly(ADP-ribose)-induced cytokine secretion Krukenberg et al. found that extracellular poly(ADP-ribose) activated cytokine secretion and phagocytosis in human and mouse macrophages through Toll-like receptors 2 and 4. This provides evidence of an extracellular function of poly(ADP-ribose).