Topical Application of a PDE4 Inhibitor Ameliorates Atopic Dermatitis through Inhibition of Basophil IL-4 Production

Phosphodiesterase (PDE) 4 inhibitors have been approved for the treatment of atopic dermatitis (AD). However, the cellular and molecular mechanisms underlying their therapeutic effect remain to be fully elucidated. Here we addressed this unsolved issue by analyzing the action of difamilast, a novel PDE4 inhibitor, on an oxazolone (OX)-induced skin allergic inflammation commonly used as a mouse model of AD. Topical application of difamilast ameliorated skin inflammation in association with reduced IL-4 expression even when the treatment commenced 4 days after the initiation of OX challenge, showing its therapeutic effect on AD. IL-4-deficient mice displayed milder skin inflammation than did WT mice, and the difamilast treatment had little or no further therapeutic effect. This was also the case in mice depleted of basophils, predominant producers of IL-4 in the skin lesion, suggesting that difamilast may act on basophils. Of note, basophils accumulating in the skin lesion showed highly upregulated expression of Pde4b encoding the B subtype of the PDE4 family. Difamilast suppressed IL-4 production from basophils activated in vitro, at least in part, through inhibition of ERK phosphorylation. Taken together, difamilast appeared to ameliorate AD inflammation through the suppression of basophil IL-4 production in the skin lesion. Phosphodiesterase (PDE) 4 inhibitors have been approved for the treatment of atopic dermatitis (AD). However, the cellular and molecular mechanisms underlying their therapeutic effect remain to be fully elucidated. Here we addressed this unsolved issue by analyzing the action of difamilast, a novel PDE4 inhibitor, on an oxazolone (OX)-induced skin allergic inflammation commonly used as a mouse model of AD. Topical application of difamilast ameliorated skin inflammation in association with reduced IL-4 expression even when the treatment commenced 4 days after the initiation of OX challenge, showing its therapeutic effect on AD. IL-4-deficient mice displayed milder skin inflammation than did WT mice, and the difamilast treatment had little or no further therapeutic effect. This was also the case in mice depleted of basophils, predominant producers of IL-4 in the skin lesion, suggesting that difamilast may act on basophils. Of note, basophils accumulating in the skin lesion showed highly upregulated expression of Pde4b encoding the B subtype of the PDE4 family. Difamilast suppressed IL-4 production from basophils activated in vitro, at least in part, through inhibition of ERK phosphorylation. Taken together, difamilast appeared to ameliorate AD inflammation through the suppression of basophil IL-4 production in the skin lesion.