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FOXO-dependent regulation of innate immune homeostasis


The innate immune system represents an ancient host defence mechanism that protects against invading microorganisms. An important class of immune effector molecules to fight pathogen infections are antimicrobial peptides (AMPs) that are produced in plants and animals1. In Drosophila, the induction of AMPs in response to infection is regulated through the activation of the evolutionarily conserved Toll and immune deficiency (IMD) pathways2. Here we show that AMP activation can be achieved independently of these immunoregulatory pathways by the transcription factor FOXO, a key regulator of stress resistance, metabolism and ageing. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation, using insulin signalling mutants, or by applying small molecule inhibitors. AMP induction is lost in foxo null mutants but enhanced when FOXO is overexpressed. Expression of AMP genes in response to FOXO activity can also be triggered in animals unable to respond to immune challenges due to defects in both the Toll and IMD pathways. Molecular experiments at the Drosomycin promoter indicate that FOXO directly binds to its regulatory region, thereby inducing its transcription. In vivo studies in Drosophila, but also studies in human lung, gut, kidney and skin cells indicate that a FOXO-dependent regulation of AMPs is evolutionarily conserved. Our results indicate a new mechanism of cross-regulation of metabolism and innate immunity by which AMP genes can be activated under normal physiological conditions in response to the oscillating energy status of cells and tissues. This regulation seems to be independent of the pathogen-responsive innate immunity pathways whose activation is often associated with tissue damage and repair. The sparse production of AMPs in epithelial tissues in response to FOXO may help modulating the defence reaction without harming the host tissues, in particular when animals are suffering from energy shortage or stress.

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Figure 1: Expression of AMPs is dependent on nutrition and insulin signalling.
Figure 2: Transcription of AMPs is directly regulated by FOXO.
Figure 3: FOXO-dependent AMP regulation in barrier epithelia of Drosophila and vertebrates.


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For sending flies and constructs, we thank M. Tatar (foxo21, foxoW24 and UAS foxoTM), B. Lemaitre (RelishE20, spätzleRM7), S. Cohen (UAS foxo–GFP) and M. Boutros (luciferase vectors). Thanks to M. Famulok for providing the Steppke inhibitor SecinH3. N. Novak, J. Grell and A. Schmitz assisted with luciferase assays. We thank S. Mario-Wegner for help with transgenic luciferase flies. We thank members of the Famulok, Schultze and Hoch laboratory for discussions. This work was supported by grants from the DFG to M.H. (SFBs 645 and 704).

Author Contributions T.B. did AMP expression studies in Drosophila, promoter analysis, reporter gene expression studies, luciferase assays in larvae and tissue-dependent AMP expression. P.C. performed in situ hybridization experiments and clonal analysis. I.Z. cloned the wild-type and deletion luciferase constructs and made transgenic flies. G.L., T.B. and A.C.A. made the mutated luciferase constructs. I.Z. and G.L. performed luciferase assays in cell culture. M.B. did EMSA band shift assays. A.C.A. and T.I. analysed Drs-like defensin and defensin expression in mammalian cell lines. M.H. supervised the research project and experimental design, M.H. and J.L.S. jointly supervised the work in mammalian cell lines. All authors discussed the experimental results. T.B. and M.H. wrote the manuscript.

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Correspondence to Michael Hoch.

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Becker, T., Loch, G., Beyer, M. et al. FOXO-dependent regulation of innate immune homeostasis. Nature 463, 369–373 (2010).

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