title: IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis.
abstract: BACKGROUND
  Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory and warrant a better understanding of GPP pathogenesis.
  
  
  OBJECTIVE
  We sought to understand better the disease mechanism of GPP to allow improved targeted therapies.
  
  
  METHODS
  We performed a gene expression study on formalin-fixed paraffin-embedded GPP (n = 28) and PV (n = 12) lesional biopsies and healthy control (n = 20) skin. Differential gene expression was analyzed using gene ontology and enrichment analysis. Gene expression was validated with quantitative RT-PCR and immunohistochemistry, and a potential disease mechanism was investigated using primary human cell culture.
  
  
  RESULTS
  Compared with healthy skin, GPP lesions yielded 479 and PV 854 differentially expressed genes, respectively, with 184 upregulated in both diseases. We detected significant contributions of IL-17A, TNF, IL-1, IL-36, and interferons in both diseases; although GPP lesions furnished higher IL-1 and IL-36 and lower IL-17A and IFN-γ mRNA expression than PV lesions did. We detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules, and we show that both neutrophils and neutrophil proteases activate IL-36. Suggesting another mechanism regulating IL-36 activity, the protease inhibitors serpin A1 and A3, which inhibit elastase and cathepsin G, respectively, were upregulated in both diseases and inhibited activation of IL-36.
  
  
  CONCLUSIONS
  Our data indicate sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a potent driver of disease pathology in GPP.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich. Electronic address: andjoh@med.umich.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich.
authors.forename: Xianying
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich.
authors.forename: Liza
authors.initials: L
authors.lastname: Wolterink
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich.
authors.forename: Drew H
authors.initials: DH
authors.lastname: Barnes
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich; Department of Dermatology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: ZhiQiang
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich.
authors.forename: Laura
authors.initials: L
authors.lastname: Reingold
authors.affiliation: Department of Rheumatology, University of Michigan, Ann Arbor, Mich.
authors.forename: J Michelle
authors.initials: JM
authors.lastname: Kahlenberg
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich; Department of Pathology, University of Michigan, Ann Arbor, Mich.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Mich.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015603:Keratinocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011565:Psoriasis / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000276:immunology
chemical_list: D016207:Cytokines; D012333:RNA, Messenger
keywords: Generalized pustular psoriasis; inflammation; interleukin; psoriasis