Unprocessed interleukin-36α regulates psoriasis-like skin inflammation in co-operation with interleukin-1

Generalized pustular psoriasis is a severe skin disease characterized by epidermal hyperplasia, neutrophil rich abscesses within the epidermis and a mixed inflammatory infiltrate in the dermis. The disease may be caused by missense mutations in the interleukin-36 receptor antagonist, IL-36Ra. Curiously, the related IL-1Ra has therapeutic effects in some of these latter patients. Here, using an experimental mouse model of psoriasiform skin inflammation, we demonstrate in vivo connections between IL-36 and IL-1 expression. After disease initiation IL-36α deficient mice exhibited dramatically diminished skin pathology, including absence of epidermal neutrophils, reduced keratinocyte acanthosis, and less dermal edema. In contrast, IL-36β and IL-36γ knockout mice developed disease indistinguishable from that of wild type mice. The endogenous IL-36α was not processed through proteolysis. While IL-36α expression was strongly induced in an IL-1 signaling-dependent manner during disease, expression of IL-1α was also dependent upon IL-36α. Hence, after being up-regulated by IL-1α, IL-36α acts through a feedback mechanism to boost IL-1α levels. Analyses of double knockout mice further revealed that IL-36α and IL-1α co-operate to promote psoriasis-like disease. In conclusion, IL-1α and IL-36α form a self-amplifying inflammatory loop in vivo that in patients with insufficient counter regulatory mechanisms may become hyper-engaged and/or chronic.