Abstract 16413: MicroRNAs Mediate Cardiac RNA-induced Inflammatory Response <i>via</i> Toll-like Receptor 7
Bibliographic record
Abstract
Introduction: We have reported that RNA released from necrotic cells induces cytokine production and may contribute to myocardial ischemia/reperfusion (I/R) injury. Our previous study has also demonstrated that RNA isolated from the heart elicits a robust cytokine response in both cardiomyocytes (CMs) and immune cells, but the type of RNA responsible for the inflammatory effect is unknown. We hypothesize that extracellular microRNAs (miRs) mediate the inflammatory effects. Methods: I/R model: mice were subjected to sham procedure or coronary occlusion for 45 min followed by reperfusion. miR array : 68 miRs in the plasma were quantified. Cytokine detection : CMs and macrophages (Mф) were treated with synthetic miRs for 18 h. Cytokines in media were measured by ELISA. miR uptake : Uptake of fluorescent-labeled miR in Mфs was detected by fluorescent microscopy and flow cytometry. miR inhibition : Locked nucleic acid-based inhibitors complementary to 6 target miRs were mixed as anti-miRs-combo. Results: Compared to the sham procedure, 31 out of 68 miRs were significantly increased by > 2-fold at 4 h following I/R. To test whether miR induces inflammatory response, we treated CMs and Mфs with selected 8 miR mimics (0.5 - 1500 nM) and found that 6 of them (miR-34a, -122, -133a, 142a, -146a, -208a) induced cytokine response in a dose-dependent manner. The effects were abolished by pre-treatment of RNase (but not DNase) and by mutations (U→A). Similar to cardiac total RNA, miR-induced cytokines was completely diminished in TLR7 -/- or MyD88 -/- , but not in TLR3 -/- or Trif -/- Mфs, and significantly inhibited by a specific TLR7 inhibitor in CMs. After incubation with fluorescent miR-133a, TLR7 -/- Mфs had similar cellular fluorescence as WT Mфs. Importantly, anti-miRs-combo significantly decreased cardiac RNA-induced cytokine production in both Mфs and CMs. Conclusions: Our data demonstrate that 1) Multiple cellular miRs are released to circulation during I/R; 2) Six miR mimics induce cytokine production specifically via TLR7-MyD88 signaling. 3) Endogenous miRs mediate in part cardiac RNA-induced cytokine response. These data suggest that cellular miRs are potent proinflammatory ligands that act through TLR7-MyD88 signaling.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".