Mechanisms of signaling between the nervous and immune systems.

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PROJECT SUMMARY/ABSTRACT Pain sensation (nociception) and immunity work together to protect animals from injury and infection. The nervous system and immune system are typically studied separately in their own subfields, however understanding the link between them is critical for the treatment of chronic pain and inflammatory diseases. This proposal bridges these fields to understand how neurons communicate with immune cells in the Drosophila model system. In Drosophila larvae, nociception is characterized by a stereotyped rolling behavior, triggered by several types of noxious stimuli, such as heat, chemicals, and mechanical force. The neurons that sense noxious input (nociceptors) tile each segment of the larval body wall. A population of hemocytes reside near peripheral neuron dendrites. After a noxious challenge, these hemocytes divide and differentiate into mature immune cells which then circulate in the hemolymph to find and encapsulate wounds and foreign invaders. Nociceptor activity is necessary for the initiation of a robust immune response, suggesting that noxious information is transmitted to hemocytes when a threat is perceived. The main hypothesis tested in this proposal is that nociceptors communicate with hemocytes through signaling at nociceptor dendrites. Neurogenic immune activation in mammals occurs through a mechanism of backwards propagating action potentials that trigger the release of proinflammatory factors from peripheral terminals. Using the precise genetic tools available in Drosophila, I aim to investigate the mechanisms of signaling between larval nociceptors and immune cells. I will investigate whether both central and peripheral nociceptive pathways contribute to neurogenic immune responses (Aim 1), and whether neuro-immune signaling involves backwards propagating action potentials and dendritic vesicle release, similar to mechanisms of neurogenic inflammation in mammals (Aim 2). A long-term goal is to use this system to identify additional molecular participants in neuro-immune communication through a nociceptor-specific screen (Future Aim 3). Results from this project will further our understanding of the proinflammatory role of nociceptors, and the mechanisms by which nociceptors induce immune responses. This will have important implications for our understanding and treatment of chronic pain and inflammatory conditions, while also elucidating general neurobiological principles that are not well understood, such as dendritic vesicle release and non-canonical action potential propagation.