Is the Nervous System More Important Than the Immune System in Itch and Atopic Dermatitis?

Atopic dermatitis is a common cutaneous disorder characterized by severe itch, chronic inflammation, and increased nerve fiber density. It has been assumed that the neural changes are in response to ongoing inflammation. We used in vivo imaging over time of fluorescently labeled peripheral sensory nerves during epicutaneous sensitization to ovalbumin in an allergic mouse model of atopic dermatitis. Visualization of cutaneous nerve branches and blood vessels sequentially over months revealed that peripheral sensory nerves begin to pathfind within 48 hours of antigen exposure. Innervation density and arbor complexity of neuropeptidergic fibers in the skin increased within days. Neural sprouting preceded changes in vascularization, vascular permeability, and immune infiltration. Blocking neural activation during periods of sensitization prevented ovalbumin-induced changes in neural recruitment and pattern reorganization, as well as subsequent inflammatory infiltrates and scratching behavior. These data implicate different roles for recently identified itch molecules in modulating various steps in the inflammatory response. Thus, in contrast to the traditional view that neural changes are reactive to inflammation and scratching, these data suggest that allergic stimulation in a chronic eczema model requires neural recruitment and activation early in the process for the elaboration and maintenance of the inflammatory cascade.