title: MicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activation.
abstract: Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARγ-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223-regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARγ/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.
authors.forename: Wei
authors.initials: W
authors.lastname: Ying
authors.forename: Alexander
authors.initials: A
authors.lastname: Tseng
authors.forename: Richard Cheng-An
authors.initials: RC
authors.lastname: Chang
authors.forename: Andrew
authors.initials: A
authors.lastname: Morin
authors.forename: Tyler
authors.initials: T
authors.lastname: Brehm
authors.forename: Karen
authors.initials: K
authors.lastname: Triff
authors.forename: Vijayalekshmi
authors.initials: V
authors.lastname: Nair
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zhuang
authors.forename: Hui
authors.initials: H
authors.lastname: Song
authors.forename: Srikanth
authors.initials: S
authors.lastname: Kanameni
authors.forename: Haiqing
authors.initials: H
authors.lastname: Wang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Golding
authors.forename: Fuller W
authors.initials: FW
authors.lastname: Bazer
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zhou
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017667:Adipocytes / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D059305:Diet, High-Fat / Q000009:adverse effects; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000502:physiology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D000077205:Pioglitazone; D011485:Protein Binding; D017154:Stromal Cells / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D020729:p120 GTPase Activating Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D018398:Homeodomain Proteins; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; C492200:Nfat5 protein, mouse; D047495:PPAR gamma; C491412:Pknox1 protein, mouse; C581321:RASA1 protein, mouse; D045162:Thiazolidinediones; D014157:Transcription Factors; D020729:p120 GTPase Activating Protein; D000077205:Pioglitazone