FOXO-dependent regulation of innate immune homeostasis

Abstract

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. 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. 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.

Integrating nutrition and immunology: A new frontier

“…With the advent of nutritional genomics (Afacan et al, 2012;Becker et al, 2010;Fellous and Lazzaro, 2010;Grayson, 2010), opportunities exist now to explore the interaction between nutrients and gene expression and their products to determine the mechanism behind disease development. This will provide significant insights into nutritional regulation of the innate immune system, the gut microbiota and pathogenesis.…”

“…Flies homozygous for the chico mutation had superior pathogen resistance to that of wild-type controls and heterozygous siblings. (Becker et al, 2010) demonstrated that anti-microbial peptides (AMP) in non-infected flies are activated in response to nuclear FOXO activity.…”

“…Also, in vivo studies indicate that the FOXO-dependent regulation of AMPs is evolutionarily conserved (see also (Becker et al, 2010;Garsin et al, 2003;Troemel et al, 2006)). Becker et al (2010) found that AMP expression was inhibited in FOXO null mutants but enhanced when FOXO was overexpressed. FOXO can directly induce the expression of the peptide by binding to the regulatory region of one of the AMP promoters (i.e., Drosomycin).…”

Disease tolerance and immunity in host protection against infection

“…FOXO activation orchestrates a metabolic response that allows essential cellular functional outputs to be maintained under sub-optimal glucose supply 151 . FOXO activation in epithelial cells regulates the expression of anti-oxidant 152 and antimicrobial genes 153 that contribute to maintain epithelial barrier integrity, acting in a protective manner against infection in flies 152, 153 and mice 153,154 . However, activation of FOXO1 and FOXO3α in muscle cells, promotes myofiber atrophy and muscle wasting associated with sepsis in mice 155 and Mycobacterium marinum infection in flies 127 .…”

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

“…Previous studies have linked the forkhead box transcription factor family O (FOXO) to innate immunity (15,16). FOXO transcription factors are highly conserved among distantly related species.…”