MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits.
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 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-κB signaling, and miR-219 targeted 5-lipoxygenase and reduced leukotriene production. RvD1 also reduced nuclear translocation of NF-κB and SMAD and down-regulated phospho-IκB. 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.
Recchiuti
Antonio
A
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Harvard Institutes of Medicine 829, Boston, MA 02115, USA.
Krishnamoorthy
Sriram
S
Fredman
Gabrielle
G
Chiang
Nan
N
Serhan
Charles N
CN
D000208:Acute Disease; D000818:Animals; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D007249:Inflammation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010538:Peritonitis / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins; D015054:Zymosan / Q000633:toxicity
D035683:MicroRNAs; D011994:Recombinant Proteins; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D015054:Zymosan