FOXO-dependent regulation of innate immune homeostasis

• Published in: Nature (London) 2010-01, Vol.463 (7279), p.369-373
• Main Authors: Becker, Thomas, Loch, Gerrit, Beyer, Marc, Zinke, Ingo, Aschenbrenner, Anna C, Carrera, Pilar, Inhester, Therese, Schultze, Joachim L, Hoch, Michael
• Format: Article
• Language: English
• Subjects: 631/208/200; 631/250/262; 631/45/612/822; Animals; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - immunology; Antimicrobial peptides; Binding sites; Biological and medical sciences; biosynthesis; DNA binding proteins; Drosophila; Drosophila melanogaster; Drosophila melanogaster - genetics; Drosophila melanogaster - immunology; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Energy Metabolism - genetics; Energy Metabolism - immunology; Energy shortages; Environmental conditions; Epithelium - immunology; Epithelium - metabolism; Evolution, Molecular; Food Deprivation; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Gene Expression Regulation; genes; Genetic aspects; Homeostasis; Homeostasis - genetics; Homeostasis - immunology; hormonal regulation; Humanities and Social Sciences; Humans; Immune response; Immune system; immunity; Immunity, Innate - genetics; Immunity, Innate - immunology; Immunobiology; insulin; Insulin - metabolism; letter; Microorganisms; Modulation of the immune response (stimulation, suppression); multidisciplinary; mutants; Pathogens; Peptides; Physiological aspects; Science; Science (multidisciplinary); Starvation; Toll-Like Receptors - immunology; transcription factors; Transcription, Genetic; Vertebrates - immunology; Vertebrates - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08698

FOXO transcription factor in innate immunity Most multicellular organisms depend on innate immunity, an ancient host defence mechanism found in both plants and animals, to fight microbial infections. Evolutionarily conserved pathways such as the Toll/Toll-like receptor and immune deficiency and tumour necrosis factor receptor pathways generate antimicrobial peptides as part of the innate immune response. This paper provides evidence that the transcription factor FOXO regulates the expression of antimicrobial peptide genes in Drosophila in response to starvation by an innate immunity independent mechanism. FOXO-dependent regulation of antimicrobial peptide expression is evolutionarily conserved in human lung, kidney and epidermis cells, suggesting that this pathway may be pivotal to maintain the epithelial defence barriers of these cells. Antimicrobial peptides (AMPs) are an important class of immune effector molecules which fight pathogen infections. AMP induction in Drosophila is regulated through the activation of the Toll and immune deficiency pathways; it is now shown that AMP activation can be achieved independently of these pathways by the transcription factor FOXO. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation. 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 animals 1 . In Drosophila , the induction of AMPs in response to infection is regulated through the activation of the evolutionarily conserved Toll and immune deficiency (IMD) pathways 2 . 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 reg