title: Self-limited versus delayed resolution of acute inflammation: temporal regulation of pro-resolving mediators and microRNA.
abstract: Mechanisms underlying delays in resolution programs of inflammation are of interest for many diseases. Here, we addressed delayed resolution of inflammation and identified specific microRNA (miR)-metabolipidomic signatures. Delayed resolution initiated by high-dose challenges decreased miR-219-5p expression along with increased leukotriene B(4) (5-fold) and decreased (~3-fold) specialized pro-resolving mediators, e.g. protectin D1. Resolvin (Rv)E1 and RvD1 (1 nM) reduced miR-219-5p in human macrophages, not shared by RvD2 or PD1. Since mature miR-219-5p is produced from pre-miRs miR-219-1 and miR-219-2, we co-expressed in human macrophages a 5-lipoxygenase (LOX) 3'UTR-luciferase reporter vector together with either miR-219-1 or miR-219-2. Only miR-219-2 reduced luciferase activity. Apoptotic neutrophils administered into inflamed exudates in vivo increased miR-219-2-3p expression and PD1/NPD1 levels as well as decreased leukotriene B(4). These results demonstrate that delayed resolution undermines endogenous resolution programs, altering miR-219-2 expression, increasing pro-inflammatory mediators and compromising SPM production that contribute to failed catabasis and homeostasis.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Li
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Nan
authors.initials: N
authors.lastname: Chiang
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D020413:3' Untranslated Regions; D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D005122:Exudates and Transudates / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism; D050356:Lipid Metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology / Q000637:transplantation; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D015230:Prostaglandin D2 / Q000378:metabolism; D034622:RNA Interference; D015054:Zymosan
chemical_list: D020413:3' Untranslated Regions; D018836:Inflammation Mediators; C578248:MIRN219 microRNA, human; D035683:MicroRNAs; D007975:Leukotriene B4; D015054:Zymosan; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone; D015230:Prostaglandin D2