| First Author | Milora KA | Year | 2015 |
| Journal | J Invest Dermatol | Volume | 135 |
| Issue | 12 | Pages | 2992-3000 |
| PubMed ID | 26203636 | Mgi Jnum | J:227570 |
| Mgi Id | MGI:5701574 | Doi | 10.1038/jid.2015.289 |
| Citation | Milora KA, et al. (2015) Unprocessed Interleukin-36alpha Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1. J Invest Dermatol 135(12):2992-3000 |
| abstractText | 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-36alpha-deficient mice exhibited dramatically diminished skin pathology, including absence of epidermal neutrophils, reduced keratinocyte acanthosis, and less dermal edema. In contrast, IL-36beta and IL-36gamma knockout mice developed disease indistinguishable from that of wild-type mice. The endogenous IL-36alpha was not processed through proteolysis. Although IL-36alpha expression was strongly induced in an IL-1 signaling-dependent manner during disease, expression of IL-1alpha was also dependent upon IL-36alpha. Hence, after being upregulated by IL-1alpha, IL-36alpha acts through a feedback mechanism to boost IL-1alpha levels. Analyses of double knockout mice further revealed that IL-36alpha and IL-1alpha cooperate to promote psoriasis-like disease. In conclusion, IL-1alpha and IL-36alpha form a self-amplifying inflammatory loop in vivo that in patients with insufficient counter regulatory mechanisms may become hyper-engaged and/or chronic. |
