A PI3K-calcium-Nox axis primes leukocyte Nrf2 to boost immune resilience and limit collateral damage

Macrophages activate the cytoprotective factor Nrf2 upon phagocytic ROS production via PI3K-calcium-Nox signaling during immune surveillance. This protective response is crucial to sustain vital immune functions and limit macrophage acquisition of senescence-like features. Macrophage Nrf2 also acts non-autonomously to limit bystander damage to adjacent healthy tissues. Phagosomal reactive oxygen species (ROS) are strategically employed by leukocytes to kill internalized pathogens and degrade cellular debris. Nevertheless, uncontrolled oxidant bursts could cause serious collateral damage to phagocytes or other host tissues, potentially accelerating aging and compromising host viability. Immune cells must, therefore, activate robust self-protective programs to mitigate these undesired effects, and yet allow crucial cellular redox signaling. Here, we dissect in vivo the molecular nature of these self-protective pathways, their precise mode of activation, and physiological effects. We reveal Drosophila embryonic macrophages activate the redox-sensitive transcription factor Nrf2 upon corpse engulfment during immune surveillance, downstream of calcium- and PI3K-dependent ROS release by phagosomal Nox. By transcriptionally activating the antioxidant response, Nrf2 not only curbs oxidative damage but preserves vital immune functions (including inflammatory migration) and delays the acquisition of senescence-like features. Strikingly, macrophage Nrf2 also acts non-autonomously to limit ROS-induced collateral damage to surrounding tissues. Cytoprotective strategies may thus offer powerful therapeutic opportunities for alleviating inflammatory or age-related diseases.

Automated summary

Macrophages activate the cytoprotective factor Nrf2 through the PI3K-calcium-Nox signaling pathway to counteract the production of reactive oxygen species (ROS) during immune surveillance. This protective response is crucial for maintaining immune function and delaying macrophage aging. Additionally, macrophage Nrf2 acts non-autonomously to protect surrounding tissues from collateral damage induced by ROS.