IMMCEPTION · Nociception and sensory nerves as regulators of type 2 immunity and skin inflammation

Preserving skin homeostasis depends on complex interactions among structural cells, immune cells, and the environment. Dysregulation of this delicate equilibrium contributes to the development of type 2 immunity-associated skin inflammation (i.e., allergic skin inflammation), including atopic dermatitis (AD). The skin is a complex organ harboring various tissue-resident immune cells (e.g., dendritic cells, mast cells and macrophages) and innervated by a meshwork of sensory nerves, including those involved in nociception (i.e., nociceptors), which respond to injurious or potentially damaging stimuli by transmitting signals to the spinal cord and brain. Despite their role in the transmission of sensation, recent evidences have suggested that nociceptors could be powerful regulators of ongoing immune response.We wish to use sophisticated mouse models and new in vivo imaging approaches to define the roles of subsets of dermal nociceptors, cationic neuropeptide substance P, dermal mast cells expressing the recently discovered receptor for cationic molecules Mas-related G protein-coupled receptor b2 (i.e., Mrgprb2), in a mouse model of AD that has many pathological, immunological, and gene expression similarities with the corresponding human disorder. We also will define the translational relevance of our mouse studies by performing parallel analyzes of nociceptors and mast cells in the lesional skin of patients from USA and France with clinically-established AD. To accomplish these goals, we have proposed herein a body of work that is solidly based on our preliminary data, with four Aims that will test innovative hypotheses by using informative genetic approaches, as well as new intravital imaging systems we recently developed.This work thus will address significant gaps in our knowledge about the pathophysiology of AD and has the potential to identify such neuro-immune interactions as a promising new therapeutic target in AD and perhaps other allergic disorders.