Peripheral Neuro-immune Interactions in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by clinical manifestations of dry skin, chronic eczema and severe itching, often combined with asthma and allergic rhinitis. AD can affect as many as 20% of children and 1–3% of adults. Skin barrier dysfunction, inflammatory and immunological abnormalities have long been noted in patients with AD. However, conflicting evidence suggests that enhanced innervation of sensory neurons may contribute to disease pathology in AD. To better understand this phenomenon, we investigated the role of sensory neurons and their relationship with mast cells in itch sensations at different ages of AD initiation. AD was induced by epicutaneous exposure of extracts from Aspergillus fumigatus (ASP) in a sensory neuron reporter animal (Pirt;tdTomato) initiated either at postnatal day14 (P14) or P35. Mice were exposed to ASP extract (or saline) for 3 weeks via patches on the back skin. We performed immunohistochemistry on back skin for mast cell protease 6 (MCPT-6), assessed trans-epidermal water loss (TEWL), and determined scratching behaviors using an artificial intelligence system. We demonstrated an increased total innervation in the skin of ASP treated mice started at P35 but not at P14. There was significant increase in TEWL and thickness of epidermal layers in both AD groups. However, increased thickening at P35 was 2x greater than that observed at P14. This resulted in decreased sensory innervation density specifically in the epidermal layer at P35. We also found increased MCs at the epidermal/dermal border in both ASP treated groups. Surprisingly, ASP treated mice at P14 did not develop robust scratching behaviors as observed at P35. Results suggest that distinctions in innervation density in the epidermis vs dermis in association with MCs may underlie scratching behaviors that contribute to AD progression and could reveal novel treatment strategies for AD. Grant support from 5U19 AI70235-15 R01NS105715 R01NS113965.