Adenosine regulates multiple physiological processes through the activation of four receptor subtypes, of which the A_2B adenosine receptor (A_2BAR) has the lowest affinity for adenosine. Being the adenosine receptor subtype most prominently expressed in epidermis, we recently described the antiproliferative and anti-inflammatory effect of the selective A_2BAR agonist BAY60–6583 (BAY) in human keratinocytes stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA), so we sought to establish the effect of topical application of BAY in a model of murine epidermal hyperplasia.

Topical application of BAY (1 or 10 μg/site) prevented the inflammatory reaction and skin lesions induced by TPA, minimizing hyperproliferation and acanthosis, as well as the expression of specific markers of proliferative keratinocytes. On the other hand, pre-treatment with the selective A_2BAR antagonist, PSB-1115 (PSB, 5 or 50 μg/site) reversed these beneficial effects. Additionally, BAY application normalized the expression of epidermal barrier proteins, whose integrity is altered in inflammatory skin diseases, while treatment with the antagonist alone worsened it.

Our results, besides confirming the anti-inflammatory and antiproliferative effects of the A2BAR agonist, further demonstrate a role of A_2BAR activation to preserve the epidermal barrier. Therefore, the activation of A_2BAR may constitute a possible new pharmacological target for the treatment of skin inflammatory diseases such as psoriasis.