title: Unprocessed Interleukin-36α Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology and Temple Autoimmunity Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Katelynn A
authors.initials: KA
authors.lastname: Milora
authors.affiliation: Department of Microbiology and Immunology and Temple Autoimmunity Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Hangfei
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Microbiology and Immunology and Temple Autoimmunity Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ornella
authors.initials: O
authors.lastname: Dubaz
authors.affiliation: Department of Microbiology and Immunology and Temple Autoimmunity Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA. Electronic address: liselott@temple.edu.
authors.forename: Liselotte E
authors.initials: LE
authors.lastname: Jensen
mesh_terms: D000038:Abscess / Q000209:etiology; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000502:physiology; D003872:Dermatitis / Q000209:etiology* / Q000276:immunology; D004817:Epidermis / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D020381:Interleukin-17 / Q000502:physiology; D053582:Interleukin-1alpha / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D011565:Psoriasis / Q000209:etiology* / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D007375:Interleukin-1; D020381:Interleukin-17; D053582:Interleukin-1alpha; C543716:interleukin 1F6, mouse