Plasticity of leukocytic exudates in resolving acute inflammation is regulated by MicroRNA and proresolving mediators.
The magnitude and duration of acute inflammation are controlled by active resolution programs involving specialized proresolving mediators (SPMs; resolvins and maresins) and microRNAs (miRNAs). Here, we report that miR-466l was temporally regulated in murine exudate-infiltrating leukocytes. Neutrophil miR-466l overexpression in vivo promoted initiation of inflammation that anteceded macrophage expression of this miRNA, which accelerated resolution when overexpressed. In macrophages, miR-466l overexpression increased prostanoids and SPMs (e.g., resolvin D1 [RvD1] and RvD5), which enhanced resolution. RvD1, RvD2, maresin 1 (MaR1), and apoptotic neutrophils reduced miR-466l expression within human macrophages, a feedback regulation that most likely prepares for homeostasis. miR-466l was upregulated in peripheral blood of sepsis patients, and its increase correlated with nonsurvival from sepsis. SPMs and miR-466l regulated transcription factors activator protein 1 and nuclear factor κB1 in miRNA biogenesis. These results demonstrate pivotal roles for SPMs and miR-466l in dynamic leukocyte plasticity during resolution of acute inflammatory responses.
Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Yongsheng
Y
Li
Jesmond
J
Dalli
Nan
N
Chiang
Rebecca M
RM
Baron
Carolina
C
Quintana
Charles N
CN
Serhan
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002633:Chemotaxis / Q000502:physiology; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology; D018805:Sepsis / Q000097:blood* / Q000401:mortality; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D015054:Zymosan / Q000633:toxicity
D018836:Inflammation Mediators; C585904:MIRN466 microRNA, human; D035683:MicroRNAs; C576133:Mirn466 microRNA, mouse; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D004281:Docosahexaenoic Acids; D015054:Zymosan