Intestinal FoxO signaling is required to survive oral infection in Drosophila

Abstract

The intestinal immune system is tailored to fight pathogens effectively while tolerating the indigenous microbiota. Impairments of this homeostatic interaction may contribute to the etiology of various diseases including inflammatory bowel diseases. However, the molecular architecture underlying this complex regulatory interaction is not well understood. Here, we show that the fruit fly Drosophila melanogaster has a multilayered intestinal immune system that ensures strictly localized antimicrobial responses. Enterocytes, a major cell population of the intestine, produced antimicrobial peptides (AMPs) in a FoxO- but not NF-κB-dependent manner. Consequently, animals impaired in FoxO-mediated signaling had a significantly lowered resistance to intestinal infections; they were unable to increase the expression of AMP genes and males showed an increased bacterial load in response to an infection. Conventional innate immune signaling converging onto NF-κB activation was operative in only a few regions of the intestine, comprising the proventriculus, copper cells, and intestinal stem cells. Taken together, our results imply that danger-mediated as well as conventional innate immune signaling constitute modules that contribute to the fruit fly's intestinal immune system. We propose that this special architecture ensures localized and efficient antimicrobial responses against invasive pathogens while preserving the microbiota.

Antimicrobial peptides extend lifespan in Drosophila

“…Loss and gain-of-function studies in adult flies indicate that Dro can be activated by dFOXO in the midgut improving the immune response (unpublished data). This hypothesis is also supported by a recent study showing that dFOXO signaling leads to AMP induction and is required to survive oral infections [45]. Taken together our findings provide new insights into the network of metabolism, innate immunity, homeostasis and ageing, helping to understand the complex relationship of these fields of research.…”

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

“…FOXO regulates antimicrobial peptide expression in the fly, and in human cell culture assays (Becker et al, 2010;Fink et al, 2016). Our data support the hypothesis that a systemic decrease in insulin signaling results in FOXO-induced expression of antimicrobial peptide and improved immunity for the host.…”

Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice

“…Bim is known to be activated by a wide range of apoptotic stimuli at the transcriptional level in a FOXO3-dependent manner4748. FOXO ensures the survival of maximal numbers of naïve T cells33, modulates helper T-cell quiescence34, and prevents inflammation-induced apoptosis of neutrophils35 that contributes to intestinal resistance against infection and preservation of the microbiota58. FOXO plays a key role in T-cell homeostasis and regulation of inflammation and immunity596061.…”