Project summary Maintenance of homeostasis at barrier tissues is essential for mammalian health. At these sites, the concerted communication of different cell lineages is central for integrating a wide range of signals, to promote responses against noxious stimuli while preventing exacerbated responses against benign stimuli. The skin represents an organ where neuro-immune interactions may be of major biological significance, as it is one of the largest interfaces between the body and the environment, integrating signals including temperature, mechanical stimulus, tissue damage, and pathogenic and commensal microbes. Both the nervous and immune systems are involved in sensing potentially damaging perturbations and mounting appropriate responses for the avoidance and clearance of noxious stimuli. Recently, we successfully identified the existence of a cellular neuro-immune circuit formed by the interaction of sensory neurons and regulatory T cells (Treg cells). This neuro-immune circuit between Treg cells and sensory nerves is mediated at least partially through Treg cell production of enkephalins, endogenous opioids that induce analgesia. Through enkephalin production Treg cells dampen nociceptor activation to prevent exacerbated skin inflammation. We additionally find that other non-neuronal skin resident populations can produce enkephalins. The work proposed in this application seeks to uncover how endogenous opioid signaling mediates communication between sensory neurons and immune cells to regulate immune homeostasis in the skin. Understanding the roles for distinct sources of endogenous opioids may lead to the therapeutic harnessing of these for the treatment of chronic conditions, and may provide alternatives to the use of exogenous opioids. In addition, this project will, at a global scale, dissect the heterogeneity of responses in neuronal populations innervating the skin to different pathological contexts, and how these responses relate to their interactions with immune cells. This project will provide new insights on the molecular underpinnings of endogenous analgesics’ role in tissue homeostasis, as well as further our understanding on how sensory neurons respond to different types of inflammation, two key concepts that may have major implications on novel therapies for chronic conditions involving pain, itch and inflammation.