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