Crisaborole Inhibits Itch and Pain by Preventing Neutrophil Infiltration in a Mouse Model of Atopic Dermatitis

Crisaborole, a phosphodiesterase 4 (PDE4) inhibitor, has been approved for the treatment of mild to moderate atopic dermatitis. Atopic dermatitis is often associated with increased pain. Using a mouse model, this study investigated whether crisaborole suppresses pain associated with atopic dermatitis and the potential mechanisms underlying it. The mouse model for atopic dermatitis was developed by repeatedly applying MC903. MC903-treated mice had increased spontaneous scratching (itch-related behaviour) and wiping behaviour (pain-related behaviour). Crisaborole was topically applied to the cheek skin of MC903-treated mice, and it reduced both itch- and pain-related behaviours in these mice. Immunofluorescence staining revealed that crisaborole reduced neutrophil infiltration and interaction of neutrophils with sensory neurones. Intradermal injection of S100A8/A9, proinflammatory neutrophil mediator, enhanced not only itch-related behaviours evoked by histamine or chloroquine, but also pain-related behaviours evoked by capsaicin. Calcium imaging of mouse dorsal root ganglion neurones revealed that pretreatment with S100A8/A9 significantly increased calcium responses to histamine and capsaicin, and the proportion of chloroquine-sensitive neurones. These findings suggest that the PDE4 inhibitor reduces itch and pain, in part by inhibiting infiltration of S100A8/A9-containing neutrophils in a mouse model of MC903-induced atopic dermatitis. SIGNIFICANCE Atopic dermatitis is often associated with itch as well as increased pain. While the precise mechanisms underlying the effectiveness of crisaborole, a US Food and Drug Administration-approved drug for atopic dermatitis, are not completely understood, this study reveals important insights. It found that crisaborole reduces the infiltration of neutrophils into the epidermis in a mouse model of MC903-induced atopic dermatitis. In addition, the study highlights a potential role of S100A8/A9, proinflammatory neutrophil mediator, in facilitating itch- and pain-related behaviours via direct action on murine sensory neurones. It appears that crisaborole may alleviate itch and pain by inhibiting the neutrophils – S100A8/A9 – sensory neurone axis in the mouse model.