Feedback coordination of FoxO-mediated antibacterial immunity by PDGF/VEGF signaling establishes hemolymph microbiota homeostasis in shrimp

A balanced immune response is required to limit the microbes without causing damage to the host. The forkhead box O (FoxO)-mediated immunity plays a pivotal role in maintaining microbiota homeostasis by regulating the expression of antimicrobial effectors in non-infected arthropods. However, the mechanism by which FoxO activity is appropriately coordinated remains unclear. In this study, we elucidated a feedback loop that coordinates FoxO-mediated antibacterial response using shrimp as a model. In this feedback loop, the commensal hemolymph microbiota maintains basal activation of FoxO, which determines the expression of antimicrobial effectors, platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF)-related factor 1 (Pvf1) and PDGF/VEGF-related receptor 4 (Pvr4). This ligand-receptor system enhances phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt) activity, limiting the excessive activation of FoxO and expression of antimicrobial effectors. This feedback loop is essential for maintaining the equilibrium of the microbiota, and its strength increases following a pathogenic infection, reducing the incidence of infection-induced mortality and tissue damage. This study revealed a microbiota-initiated feedback loop that balances FoxO-mediated antibacterial immunity for the establishment of microbiota homeostasis, and provides new insights into the functional diversification of PDGF/VEGF signaling.