title: Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor.
abstract: The extracellular nuclear proteins, histone H4 (H4) and high mobility group box 1 (HMGB1), released by injured cells during the activation of inflammation and coagulation pathways provoke potent inflammatory responses through interaction with pathogen-related pattern recognition receptors (ie, Toll-like receptors [TLRs] and receptor for advanced glycation end products [RAGE]) present on vascular and innate immune cells. Inorganic polyphosphate (polyP) has emerged as a key modulator of coagulation and inflammation. Here, we demonstrate that polyP binds to both H4 and HMGB1 with high affinity, thereby dramatically potentiating their proinflammatory properties in cellular and in vivo models. By using small interfering RNA knockdowns, pharmacologic inhibitors and extracellular domains of the receptors TLR2, TLR4, RAGE, and P2Y1 as competitive inhibitors, we demonstrate that polyP amplifies H4- and HMGB1-mediated inflammatory signaling in human umbilical vein endothelial cells specifically through interaction with the RAGE and P2Y1 receptors, thereby eliciting intracellular Ca(2+) release. Finally, we demonstrate that the natural anticoagulant protease, activated protein C, potently inhibits polyP-mediated proinflammatory effects of both nuclear proteins in cellular and in vivo systems.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO.
authors.forename: Peyman
authors.initials: P
authors.lastname: Dinarvand
authors.forename: Seyed Mahdi
authors.initials: SM
authors.lastname: Hassanian
authors.forename: Shabir H
authors.initials: SH
authors.lastname: Qureshi
authors.forename: Chandrashekhara
authors.initials: C
authors.lastname: Manithody
authors.forename: Joel C
authors.initials: JC
authors.lastname: Eissenberg
authors.forename: Likui
authors.initials: L
authors.lastname: Yang
authors.forename: Alireza R
authors.initials: AR
authors.lastname: Rezaie
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011122:Polyphosphates / Q000494:pharmacology*; D011486:Protein C / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D006657:Histones; D018836:Inflammation Mediators; D011122:Polyphosphates; D011486:Protein C; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D058472:Receptors, Purinergic P2Y1; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D002118:Calcium