Induction of IL-4Rα-dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo.

Dominik Ruckerl, Stephen J Jenkins, Nouf N Laqtom, Iain J Gallagher, Tara Sutherland, Sheelagh Duncan, Amy H Buck, Judith Allen

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157 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)2307-2316
Issue number11
Publication statusPublished - 13 Sept 2012

Bibliographical note

The authors thank Yvonne Harcus for excellent technical assistance, Martin Waterfall for performing outstanding FACS sorting, and Frank Brombacher for providing the IL-4Rα−/− mice.

This work was funded by the Medical Research Council United Kingdom (MRC-UK G0600818) and the Wellcome Trust (Center for Immunity, Infection and Evolution; 082611/Z/07/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

082611/Z/07/Z, Wellcome Trust, United Kingdom
095831, Wellcome Trust, United Kingdom
G0600818, Medical Research Council, United Kingdom


  • mice
  • micrornas
  • macrophages
  • signal transduction
  • proto-oncogene proteins c-akt
  • 1-phosphatidylinositol 3-kinase


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