An Innate Immune Receptor Toll-1 converts chronic light stress into glial phagocytosis

Chronic stress can cause progressive neuronal degeneration, yet the molecular mechanisms linking stress sensing to neuroimmune responses remain elusive. In this study, a Drosophila model of chronic light-induced stress, we show that photoreceptor neurons accumulate reactive oxygen species (ROS) and exhibit Toll-1 activation, in association with Spatzle ligands and receptor endocytosis. Toll-1 activation in neurons promotes axonal degeneration by inducing expression of the glial phagocytic receptor Draper (Drpr), leading to the engulfment of stressed axons. Genetic interaction analyses indicate that Toll-1 functions upstream of Drpr in a stress-responsive signaling cascade. Importantly, blocking either Toll-1 or Drpr attenuates axon loss under light stress, highlighting their essential roles. Our findings reveal a neuron-glia communication axis in which neuronal innate immune signaling instructs glial phagocytosis, converting sustained environmental stress into structural degeneration. This study provides a mechanistic framework for sterile neurodegeneration and offers insights into how immune receptors regulate nervous system integrity under non-infectious conditions.