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MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits.

ABSTRACT: Mechanisms controlling resolution of acute inflammation are of wide interest. Here, we investigated microRNAs (miRNAs) in self-limited acute inflammatory exudates and their regulation by resolvin D1 (RvD1). Using real-time PCR analysis, we found in resolving exudates that miR-21, miR-146b, miR-208a, miR-203, miR-142, miR-302d, and miR-219 were selectively regulated (P<0.05) in self-limited murine peritonitis. RvD1 (300 ng/mouse or 15 ?g kg(-1)) reduced zymosan-elicited neutrophil infiltration into the peritoneum 25-50% and shortened the resolution interval (R(i)) by ?4 h. In peritonitis at 12 h, RvD1 up-regulated miR-21, miR-146b, and miR-219 and down-regulated miR-208a in vivo. In human macrophages overexpressing recombinant RvD1 receptors ALX/FPR2 or GPR32, these same miRNAs were significantly regulated (P<0.05) by RvD1 at concentrations as low as 10 nM, recapitulating the in vivo circuit. In addition, RvD1-miRNAs identified herein target cytokines and proteins involved in the immune system, e.g., miR-146b targeted NF-?B signaling, and miR-219 targeted 5-lipoxygenase and reduced leukotriene production. RvD1 also reduced nuclear translocation of NF-?B and SMAD and down-regulated phospho-I?B. Taken together, these results indicate that resolvin-regulated specific miRNAs target genes involved in resolution and establish a novel resolution circuit involving RvD1 receptor-dependent regulation of specific miRNAs.

SUBMITTER: Recchiuti A

PROVIDER: S-EPMC3023392 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits.

Recchiuti Antonio A Krishnamoorthy Sriram S Fredman Gabrielle G Chiang Nan N Serhan Charles N CN

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20101018 2

Mechanisms controlling resolution of acute inflammation are of wide interest. Here, we investigated microRNAs (miRNAs) in self-limited acute inflammatory exudates and their regulation by resolvin D1 (RvD1). Using real-time PCR analysis, we found in resolving exudates that miR-21, miR-146b, miR-208a, miR-203, miR-142, miR-302d, and miR-219 were selectively regulated (P<0.05) in self-limited murine peritonitis. RvD1 (300 ng/mouse or 15 μg kg(-1)) reduced zymosan-elicited neutrophil infiltration in ...[more]

PMID: 20956612

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Project description:AimsInflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD.Methods and resultsPulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes.ConclusionThe inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

Dataset Information

MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits.

Publications

MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits.

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