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 IL-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 l... More
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 IL-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. Although 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 upregulated 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 cooperate 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.
