title: Nucleic acid-binding polymers as anti-inflammatory agents.
abstract: Dead and dying cells release nucleic acids. These extracellular RNAs and DNAs can be taken up by inflammatory cells and activate multiple nucleic acid-sensing toll-like receptors (TLR3, 7, 8, and 9). The inappropriate activation of these TLRs can engender a variety of inflammatory and autoimmune diseases. The redundancy of the TLR family encouraged us to seek materials that can neutralize the proinflammatory effects of any nucleic acid regardless of its sequence, structure or chemistry. Herein we demonstrate that certain nucleic acid-binding polymers can inhibit activation of all nucleic acid-sensing TLRs irrespective of whether they recognize ssRNA, dsRNA or hypomethylated DNA. Furthermore, systemic administration of such polymers can prevent fatal liver injury engendered by proinflammatory nucleic acids in an acute toxic shock model in mice. Therefore these polymers represent a novel class of anti-inflammatory agent that can act as molecular scavengers to neutralize the proinflammatory effects of various nucleic acids.
authors.affiliation: Duke Translational Research Institute, Duke University Medical Center, Durham, NC 27710, USA. jaewoo.lee@duke.edu
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Jang Wook
authors.initials: JW
authors.lastname: Sohn
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kam W
authors.initials: KW
authors.lastname: Leong
authors.forename: David
authors.initials: D
authors.lastname: Pisetsky
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Sullenger
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002412:Cations; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D042541:Intracellular Space / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D008107:Liver Diseases / Q000150:complications / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009696:Nucleic Acids / Q000378:metabolism* / Q000633:toxicity; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011108:Polymers / Q000494:pharmacology* / Q000627:therapeutic use; D012772:Shock, Septic / Q000150:complications / Q000188:drug therapy; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; C408982:CPG-oligonucleotide; D002412:Cations; D008024:Ligands; D009696:Nucleic Acids; D009838:Oligodeoxyribonucleotides; D011108:Polymers; D051193:Toll-Like Receptors