The role of Mrgpr signaling in the development of inflammation in atopic dermatitis

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 DESCRIPTION (provided by applicant): Atopic dermatitis (AD), commonly called `eczema', is a frequently disabling cutaneous disorder characterized by intense pruritus and chronic skin inflammation. Defective epidermal barrier function and immune dysregulation have long been considered the major precipitating factors in the development of AD. However, therapeutics targeting these factors alone are frequently inadequate to control atopic disease. Growing evidence from our lab and others suggests that peripheral sensory nerves play a critical role in modulating inflammatory responses in the skin. Performing in vivo imaging in a mouse model of chronic allergic eczema, I have shown that peripheral sensory nerves undergo neural pathfinding within days in response to epicutaneous exposure to ovalbumin. Neural proliferation and upregulation of neuropeptidergic fibers precede vascular reactivity and inflammatory influx by days to weeks. Pharmacologic blockade of neural activity during periods of OVA exposure prevents eczema development. These data suggest that peripheral sensory nerves act as biosensors to detect antigen(s) in the skin and subsequently to coordinate the vasoimmune response. Members of the Mas-related G- protein coupled receptor (Mrgpr) family function as innate sensors in a subset of cutaneous nociceptive fibers to relay non-histaminergic itch and in mast cells to mediate the stimulatory effects of inflammatory peptides resulting in mast cell degranulation. These neuronal and mast cell Mrgprs respond to a variety of endogenous and exogenous stimuli, making them attractive candidate molecules for serving dual functions of antigen surveillance and immune modulation in response to offending agents. I propose to use a multimodality approach including in vitro and in vivo strategies to evaluate the role of Mrgprs in mediating neural and mast cell responses to antigenic stimulation and in propagating of cutaneous inflammation in a mouse model of allergic eczema.