title: Induction of IL-4Rα-dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo.
abstract: Macrophage (MΦ) activation must be tightly controlled to preclude overzealous responses that cause self-damage. MicroRNAs promote classical MΦ activation by blocking antiinflammatory signals and transcription factors but also can prevent excessive TLR signaling. In contrast, the microRNA profile associated with alternatively activated MΦ and their role in regulating wound healing or antihelminthic responses has not been described. By using an in vivo model of alternative activation in which adult Brugia malayi nematodes are implanted surgically in the peritoneal cavity of mice, we identified differential expression of miR-125b-5p, miR-146a-5p, miR-199b-5p, and miR-378-3p in helminth-induced MΦ. In vitro experiments demonstrated that miR-378-3p was specifically induced by IL-4 and revealed the IL-4-receptor/PI3K/Akt-signaling pathway as a target. Chemical inhibition of this pathway showed that intact Akt signaling is an important enhancement factor for alternative activation in vitro and in vivo and is essential for IL-4-driven MΦ proliferation in vivo. Thus, identification of miR-378-3p as an IL-4Rα-induced microRNA led to the discovery that Akt regulates the newly discovered mechanism of IL-4-driven macrophage proliferation. Together, the data suggest that negative regulation of Akt signaling via microRNAs might play a central role in limiting MΦ expansion and alternative activation during type 2 inflammatory settings.
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Dominik
authors.initials: D
authors.lastname: Rückerl
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Jenkins
authors.forename: Nouf N
authors.initials: NN
authors.lastname: Laqtom
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Gallagher
authors.forename: Tara E
authors.initials: TE
authors.lastname: Sutherland
authors.forename: Sheelagh
authors.initials: S
authors.lastname: Duncan
authors.forename: Amy H
authors.initials: AH
authors.lastname: Buck
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allen
mesh_terms: D000818:Animals; D017178:Brugia malayi / Q000276:immunology; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015847:Interleukin-4 / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D053662:Interleukin-4 Receptor alpha Subunit; C546119:MIRN378 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4; D058539:Phosphatidylinositol 3-Kinase; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt