title: MicroRNA-24 regulates macrophage behavior and retards atherosclerosis.
abstract: OBJECTIVE
  Our recent studies have highlighted membrane type-1 matrix metalloproteinase (MMP)-14 as a selective marker for an invasive subset of macrophages potentially related to atherosclerotic plaque progression. Moreover, colony stimulating factors (CSF) may exert divergent effects on macrophage MMP expression, possibly through microRNAs. We, therefore, aim to identify and test the pathophysiological role of microRNAs, which modulate macrophage MMP-14 expression in atherosclerotic plaque progression.
  
  
  RESULTS
  Compared with macrophage CSF-differentiated macrophages, granulocyte/macrophage CSF-matured macrophages exhibited reduced MMP-14 mRNA levels but increased protein expression and activity, which resulted in heightened macrophage invasion. MicroRNA-24, identified to target MMP-14, was accordingly increased in macrophage CSF compared with granulocyte/macrophage CSF macrophages. Silencing microRNA-24 in macrophage CSF macrophages significantly increased MMP-14 expression and enhanced their invasive capacity, mimicking granulocyte/macrophage CSF macrophages, and suggesting that granulocyte/macrophage CSF modulates MMP-14 protein expression and subsequent macrophage invasion in a microRNA-24-dependent manner. In human coronary atherosclerotic plaques, increased MMP-14 protein expression in foam cell macrophages was associated with lesions exhibiting histological characteristics associated with an unstable phenotype. Furthermore, microRNA-24 expression in these atherosclerotic plaques was inversely related to MMP-14 protein expression. Moreover, stable plaques contained higher microRNA-24 levels than unstable plaques, and microRNA-24 colocalized with foam cell macrophages that exhibited low MMP-14 protein expression. Finally, in atherosclerotic mice (apolipoprotein E-deficient), microRNA-24 inhibition increased plaque size and macrophage MMP-14 expression.
  
  
  CONCLUSIONS
  Taken together, our data demonstrates that downregulation of microRNA-24 promotes an invasive macrophage subset and plays a novel regulatory role in MMP-14 proteolytic activity and, therefore, plaque stability, highlighting its therapeutic potential.
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
authors.forename: Karina
authors.initials: K
authors.lastname: Di Gregoli
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Jenkins
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Salter
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: White
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom. jason.l.johnson@bristol.ac.uk.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D016122:Brachiocephalic Trunk; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; C529080:Mirn24 microRNA, mouse; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053511:Matrix Metalloproteinase 14
keywords: atherosclerosis; macrophages; matrix metalloproteinases; microRNAs