Alteration of the EphA2/Ephrin-a signaling axis in psoriatic epidermis

Kristin Gordon, James J. Kochkodan, Hanz Blatt, Samantha Y. Lin, Nihal Kaplan, Andrew Johnston, William R. Swindell, Paul Hoover, Bethanee J. Schlosser, James T. Elder, Johann E. Gudjonsson, Spiro Getsios*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequent downregulation by ephrin-A1 ligand. The objective of this study was to determine whether the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition in which keratinocyte differentiation is abnormal. Microarray analysis of skin biopsies from psoriasis patients revealed increased mRNA transcripts for several members of this RTK family in plaques, including the EphA1, EphA2, and EphA4 subtypes prominently expressed by keratinocytes. Of these, EphA2 showed the greatest upregulation, a finding that was confirmed by quantitative reverse-transcriptase-PCR, immunohistochemistry (IHC), and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiate in high calcium or a three-dimensional (3D) raft culture of human epidermis to a combination of growth factors and cytokines elevated in psoriasis increased EphA2 mRNA and protein expression while inducing S100A7 and disrupting differentiation. Pharmacological delivery of a soluble ephrin-A1 peptidomimetic ligand led to a reduction in EphA2 expression and ameliorated proliferation and differentiation in raft cultures exposed to EGF and IL-1α. These findings suggest that ephrin-A1-mediated downregulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation.

Original languageEnglish (US)
Pages (from-to)712-722
Number of pages11
JournalJournal of Investigative Dermatology
Volume133
Issue number3
DOIs
StatePublished - Mar 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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