期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 139, 期 4, 页码 1217-1227出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.10.021
关键词
Pustular skin disorders; neutrophils; inflammation; transcriptomic profiling; 6-transmembrane epithelial antigens of prostate; IL-1; IL-36; CXCL1; CXCL8
资金
- University of Michigan Babcock Endowment Fund
- National Institutes of Health (NIH) [K08-AR060802, R01-AR069071]
- A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award
- Doris Duke Charitable Foundation [2013106]
- Novartis
- NIH [K01 AR064765]
- National Psoriasis Foundation USA
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the NIH [K08AR063668]
Background: Pustular skin disorders are a category of difficult-to-treat and potentially life-threatening conditions that involve the appearance of neutrophil-rich pustules. The molecular basis of most pustular skin conditions has remained unknown. Objective: We sought to investigate the molecular basis of 3 pustular skin disorders: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), and acute generalized exanthematous pustulosis (AGEP). Methods: Microarray analyses were performed to profile genome-wide gene expression of skin biopsy specimens obtained from patients with GPP, PPP, or AGEP and healthy control subjects. Functional enrichment, gene network, and k-means clustering analyses were used to identify molecular pathways dysregulated in patients with these disorders. Immunohistochemistry and immunofluorescence were used to determine protein localization. Quantitative RT-PCR and ELISA were used to determine transcript and secreted cytokine levels. Small interfering RNA was used to decrease transcript levels. Results: Molecules and pathways related to neutrophil chemotaxis emerged as common alterations in patients with GPP, PPP, and AGEP, which is consistent with the pustular phenotypes. Expression of two 6-transmembrane epithelial antigens of the prostate (STEAP) proteins, STEAP1 and STEAP4, was increased in patients' skin and colocalized with IL-36 gamma around neutrophilic pustules. STEAP1/4 expression clustered with and positively correlated with that of IL-1, the IL-36 family proteins, and CXCL1/8. STEAP4 expression was activated by cytokines and suppressed by inhibition of mitogen-activated protein kinase kinase 1/2, whereas STEAP1 expression appeared less prone to such dynamic regulation. Importantly, STEAP1/4 knockdown resulted in impaired induction of a broad spectrum of proinflammatory cytokines, including IL-1, IL-36, and the neutrophil chemotaxins CXCL1 and CXCL8. STEAP1/4 knockdown also reduced the ability of keratinocytes to induce neutrophil chemotaxis. Conclusion: Transcriptomic changes in 3 pustular skin disorders, GPP, PPP, and AGEP, converged on neutrophil chemotaxis and diapedesis and cytokines known to drive neutrophil-rich inflammatory processes, including IL-1 and members of the IL-36 family. STEAP1 and STEAP4 positively regulate the induction of proinflammatory neutrophil-activating cytokines.
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