Unprocessed Interleukin-36 alpha Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1

作者：Milora Katelynn A; Fu Hangfei; Dubaz Ornella; Jensen Liselotte E^*

来源：Journal of Investigative Dermatology, 2015, 135(12): 2992-3000.

DOI：10.1038/jid.2015.289

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-36 alpha-deficient mice exhibited dramatically diminished skin pathology, including absence of epidermal neutrophils, reduced keratinocyte acanthosis, and less dermal edema. In contrast, IL-36 beta and IL-36 gamma knockout mice developed disease indistinguishable from that of wild-type mice. The endogenous IL-36 alpha was not processed through proteolysis. Although IL-36 alpha expression was strongly induced in an IL-1 signaling-dependent manner during disease, expression of IL-1 alpha was also dependent upon IL-36 alpha. Hence, after being upregulated by IL-1 alpha, IL-36 alpha acts through a feedback mechanism to boost IL-1 alpha levels. Analyses of double knockout mice further revealed that IL-36 alpha and IL-1 alpha cooperate to promote psoriasis-like disease. In conclusion, IL-1 alpha and IL-36 alpha form a self-amplifying inflammatory loop in vivo that in patients with insufficient counter regulatory mechanisms may become hyperengaged and/or chronic.

• 出版日期2015-12