View Program - 63rd Annual Drosophila Research Conference

The respiratory burst is a powerful weapon utilized by leukocytes to protect the host from dangerous pathogens and degrade cellular debris. Nevertheless, Reactive Oxygen Species (ROS) are exceptionally reactive molecules that could cause serious bystander damage to both, the phagocyte itself and the surrounding environment. Therefore, to sustain full functionality under these hostile conditions, immune cells must trigger a complex and robust self-protection program. This cytoprotective system must be carefully orchestrated to ensure leukocytes limit the undesirable side-effects of the constant oxidative challenge, while allowing low levels of ROS for crucial cellular signalling.
Here, we discuss the molecular nature of these self-protective strategies, dissecting in vivo both their precise mechanism of activation and physiological relevance. We provide evidence that Drosophila macrophages robustly activate the master redox-sensitive transcription factor Nrf2 upon apoptotic corpse engulfment and this activation is driven by calcium and PI3K-dependent release of ROS by NOX oxidases at the phagosome. We find that this Nrf2-mediated antioxidant response is vital to promote Drosophila macrophage tolerance to oxidative stress during normal homeostatic behaviour, preserving efficient basal motility and allowing a robust and timely detection of epithelial wounds. Moreover, by reducing the oxidative burden, Nrf2 not only delays the onset of immune-senescence but supports host longevity by limiting collateral damage to surrounding tissues. Overall, we find that by preserving a healthy immune system, leukocyte Nrf2 plays important paracrine effects by delaying premature systemic aging and improving organismal lifespan. We propose that future therapeutic interventions aimed to boost immune self-protection may be beneficial to delay immune aging and alleviate correlated morbidities.

Phagocytosis-dependent activation of Nrf2 strengthens the macrophage inflammatory response whilst limiting immune senescence and systemic tissue damage.