Six-transmembrane epithelial antigens of the prostate comprise a novel inflammatory nexus in patients with pustular skin disorders - 19/04/17
Abstract |
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-36γ 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.
Le texte complet de cet article est disponible en PDF.Key words : Pustular skin disorders, neutrophils, inflammation, transcriptomic profiling, 6-transmembrane epithelial antigens of prostate, IL-1, IL-36, CXCL1, CXCL8
Abbreviations used : AGEP, DEG, FFPE, GPP, MEK, PPP, STEAP, TLR
Plan
| Supported in part by the University of Michigan Babcock Endowment Fund (to A.J., Y.L, X.X., M.K.S., J.J.V., and J.E.G.), National Institutes of Health (NIH) awards K08-AR060802 and R01-AR069071 (to J.E.G.), the A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (to J.E.G.), the Doris Duke Charitable Foundation Grant no. 2013106 (to J.E.G.), and Novartis (J.E.G.). A.J. is supported by NIH grant K01 AR064765 and the National Psoriasis Foundation USA. J.M.K. was partially supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the NIH under award no. K08AR063668. |
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| Disclosure of potential conflict of interest: J. M. Kahlenberg has received grant K08 from the National Institutes of Health (NIH) and consultancy fees from Idera Pharmaceuticals. A. Johnston's institution has received grants from the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; K01 AR064765), the National Psoriasis Foundation USA, the Babcock Memorial Trust, NIH/NIAMS grants K08 AR063668 (to J.M.K.) and K08 AR060802 and R01 AR069071 to (to J.E.G.), the A. Alfred Taubman Medical Research Institute, NIH (DK100845), and a Novartis and Doris Duke Charitable Foundation grant (no. 2013106) for the work under consideration for publication; his institution has received grants for work outside the submitted work: NIH (R01 grant pending), GlaxoSmithKline (research grant RIP1Kinase inhibitors for psoriasis), the American Skin Association, Biomarkers of lower urinary tract symptoms (LUTS; US patent application no. 14/513,566). J. E. Gudjonsson's institution has received an investigator-initiated grant from Novartis for the work under consideration for publication, and for relevant financial activities outside the submitted work, she has received board membership from Novartis; consultancy fees from Pfizer, AbbVie, Novartis, and Kyowa Kirin; and stock options from NuMedii; her institution has received grants from AbbVie. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 4
P. 1217-1227 - avril 2017 Retour au numéro
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