title: Extracellular poly(ADP-ribose) is a pro-inflammatory signal for macrophages.
abstract: 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.
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kristin_krukenberg@hms.harvard.edu.
authors: Kristin A
authors: KA
authors: Krukenberg
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Sujeong
authors: S
authors: Kim
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Edwin S
authors: ES
authors: Tan
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Zoltan
authors: Z
authors: Maliga
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Timothy J
authors: TJ
authors: Mitchison
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D011064:Poly Adenosine Diphosphate Ribose / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases