A targetable, non-canonical STAT3 activation induced by the tyrosine-less region of IL-22R orchestrates imiquimod-induced psoriasis-like dermatitis in mice

Abstract Exacerbated IL-22 activity induces tissue inflammation and immune disorders such as psoriasis. However, because IL-22 is also essential for tissue repair and defense at barrier interfaces, targeting IL-22 activity to treat psoriasis bears the risk of deleterious effects at mucosal sites such as the gut. We previously showed, in vitro, that IL-22 signaling relies on IL-22Rα tyrosine–dependent and -independent pathways. The second depends on the C-terminal tyrosine-less region of IL-22Ra and leads to massive STAT3 activation. As STAT3 activation is associated with the development of psoriasis, we hypothesized that the specific inhibition of the non-canonical STAT3 activation by the tyrosine-less region of IL-22Ra could reduce psoriasis-like disease while leaving intact its tissue defense functions in the gut. We show that mice expressing a C-terminally truncated version of IL-22Ra (ΔCtermut/mut mice) are protected from the development of psoriasis-like dermatitis lesions induced by imiquimod, to a lesser extent than Il22ra-/- mice. In contrast only Il22ra-/- mice lose weight after Citrobacter rodentium infection. Altogether, our data suggests that specific targeting of the non-canonical STAT3 activation by IL-22 could serve to treat psoriasis-like skin inflammation without affecting IL-22 dependent tissue repair or barrier defense at other sites.