title: Control of the Inflammatory Macrophage Transcriptional Signature by miR-155.
abstract: Inflammatory M1 spectrum macrophages protect from infection but can cause inflammatory disease and tissue damage, whereas alternatively activated/M2 spectrum macrophages reduce inflammation and promote tissue repair. Modulation of macrophage phenotype may be therapeutically beneficial and requires further understanding of the molecular programs that control macrophage differentiation. A potential mechanism by which macrophages differentiate may be through microRNA (miRNA), which bind to messenger RNA and post-transcriptionally modify gene expression, cell phenotype and function. We hypothesized that the inflammation-associated miRNA, miR-155, would be required for typical development of macrophage inflammatory state. miR-155 was rapidly up-regulated over 100-fold in inflammatory M1(LPS + IFN-γ), but not M2(IL-4), macrophages. Inflammatory genes Inos, Il1b and Tnfa and their corresponding protein or enzymatic products were reduced up to 72% in miR-155 knockout mouse M1(LPS + IFN-γ) macrophages, but miR-155 deficiency did not affect expression of the M2-associated gene Arg1 in M2(IL-4) macrophages. Additionally, a miR-155 oligonucleotide inhibitor efficiently suppressed Inos and Tnfa gene expression in wild-type M1(LPS + IFN-γ) macrophages. Comparative transcriptional profiling of unstimulated and M1(LPS + IFN-γ) macrophages derived from wild-type (WT) and miR-155 knockout (KO) mice revealed that half (approximately 650 genes) of the signature we previously identified in WT M1(LPS + IFN-γ) macrophages was dependent on miR-155. Real-Time PCR of independent datasets confirmed that miR-155 contributed to suppression of its validated mRNA targets Inpp5d, Tspan14, Ptprj and Mafb and induction of Inos, Il1b, Tnfa, Il6 and Il12. Overall, these data indicate that miR-155 plays an essential role in driving the inflammatory phenotype of M1(LPS+ IFN-γ) macrophages.
authors.affiliation: School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Jablonski
authors.affiliation: Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Gaudet
authors.affiliation: School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Amici
authors.affiliation: Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
authors.affiliation: School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, The Ohio State University, Columbus, Ohio, United States of America.|Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America.|Department of Microbial Infection and Immunity, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mireia
authors.identifier: http://orcid.org/0000-0002-0600-4593
authors.initials: M
authors.lastname: Guerau-de-Arellano
mesh_terms: D000818:Animals; D015415:Biomarkers; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D012333:RNA, Messenger