Optical control of adenosine A3 receptor function in psoriasis

Psoriasis is a chronic and relapsing inflammatory skin disease lacking a cure that affects approximately 2% of the population. Defective keratinocyte proliferation and differentiation, and aberrant immune responses are major factors in its pathogenesis. Available treatments for moderate to severe psoriasis are directed to immune system causing systemic immunosuppression over time, and thus concomitant serious side effects (i.e. infections and cancer) may appear. In recent years, the G(i) protein-coupled A(3) receptor (A(3)R) for adenosine has been suggested as a novel and very promising therapeutic target for psoriasis. Accordingly, selective, and high affinity A(3)R agonists are known to induce robust anti-inflammatory effects in animal models of autoimmune inflammatory diseases. Here, we demonstrated the efficacy of a selective A3R agonist, namely MRS5698, in preventing the psoriatic-like phenotype in the IL-23 mouse model of psoriasis. Subsequently, we photocaged this molecule with a coumarin moiety to yield the first photosensitive A(3)R agonist, MR57344, which in photopharmacological experiments prevented the psoriatic-like phenotype in the IL-23 animal model. Thus, we have demonstrated the feasibility of using a non-invasive, site-specific, light-directed approach to psoriasis treatment.

Automated summary

Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population, with defective keratinocyte proliferation and differentiation, along with aberrant immune responses being major factors in its pathogenesis. Current treatments for moderate to severe psoriasis may lead to systemic immunosuppression and serious side effects, such as infections and cancer. In recent years, the A(3) receptor for adenosine has emerged as a promising therapeutic target for psoriasis, showing robust anti-inflammatory effects in animal models of autoimmune inflammatory diseases.