Cardiac RNA Induces Inflammatory Responses in Cardiomyocytes and Immune Cells via Toll-like Receptor 7 Signaling

被引:55
作者
Feng, Yan [1 ]
Chen, Hongliang [1 ]
Cai, Jiayan [1 ]
Zou, Lin [1 ]
Yan, Dan [1 ]
Xu, Ganqiong [1 ]
Li, Dan [1 ]
Chao, Wei [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA 02114 USA
基金
美国国家卫生研究院;
关键词
POTENTIAL BIOMARKER; MESSENGER-RNA; CIRCULATING MICRORNAS; PATTERN-RECOGNITION; MYOCARDIAL INJURY; DENDRITIC CELLS; NECROTIC CELLS; NUCLEIC-ACIDS; CUTTING EDGE; STRANDED-RNA;
D O I
10.1074/jbc.M115.661835
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have recently reported that extracellular RNA (exRNA) released from necrotic cells induces cytokine production in cardiomyocytes and immune cells and contributes to myocardial ischemia/reperfusion injury. However, the signaling mechanism by which exRNA exhibits its pro-inflammatory effect is unknown. Here we hypothesize that exRNA directly induces inflammation through specific Toll-like receptors (TLRs). To test the hypothesis, we treated rat neonatal cardiomyocytes, mouse bone marrow-derived macrophages (BMDM), or mouse neutrophils with RNA (2.5-10 mu g/ml) isolated from rat cardiomyocytes or the hearts from mouse, rat, and human. We found that cellular RNA induced production of several cytokines such as macrophage inflammatory protein-2 (MIP-2), ILs, TNF alpha, and the effect was completely diminished by RNase, but not DNase. The RNA-induced cytokine production was partially inhibited in cells treated with TLR7 antagonist or genetically deficient in TLR7. Deletion of myeloid differentiation primary response protein 88 (MyD88), a downstream adapter of TLRs including TLR7, abolished the RNA-induced MIP-2 production. Surprisingly, genetic deletion of TLR3 had no impact on the RNA-induced MIP-2 response. Importantly, extracellular RNA released from damaged cardiomyocytes also induced cytokine production. Finally, mice treated with 50 mu g of RNA intraperitoneal injection exhibited acute peritonitis as evidenced by marked neutrophil and monocyte migration into the peritoneal space. Together, these data demonstrate that exRNA of cardiac origin exhibits a potent pro-inflammatory property in vitro and in vivo and that exRNA induces cytokine production through TLR7-MyD88 signaling.
引用
收藏
页码:26688 / 26698
页数:11
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