Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor

被引:96
作者
Dinarvand, Peyman [1 ]
Hassanian, Seyed Mahdi [1 ]
Qureshi, Shabir H. [1 ]
Manithody, Chandrashekhara [1 ]
Eissenberg, Joel C. [1 ]
Yang, Likui [1 ]
Rezaie, Alireza R. [1 ]
机构
[1] St Louis Univ, Sch Med, Edward A Doisy Dept Biochem & Mol Biol, St Louis, MO 63104 USA
基金
美国国家卫生研究院;
关键词
INORGANIC POLYPHOSPHATE; EXTRACELLULAR HISTONES; THERAPEUTIC TARGET; ENDOTHELIAL-CELLS; SEVERE SEPSIS; C PATHWAY; HMGB1; RAGE; INFLAMMATION; ANTICOAGULANT;
D O I
10.1182/blood-2013-09-529602
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 P2Y(1) 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 P2Y(1) receptors, thereby eliciting intracellular Ca2+ 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.
引用
收藏
页码:935 / 945
页数:11
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