Alteration of the EphA2/Ephrin-A Signaling Axis in Psoriatic Epidermis

Abstract

EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequently down-regulation by ephrin-A1 ligand. The objective for this study was to determine if the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition where 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 up-regulation, a finding that was confirmed by quantitative RT-PCR, IHC analysis and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiated in high calcium or a 3-dimensiosnal 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 down-regulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation.

Eph receptor and ephrin function in breast, gut, and skin epithelia

“…These lesions show a marked increase in EphA2 levels coincident with a reduction in ephrin-A1 and ephrin-A3 expression. 123 Similarly, EphA2 was increased by a variety of growth factors and proinflammatory cytokines, including epidermal growth factor, interleukin-1a and TNFa, in a 3-dimensional organotypic culture model of human epidermis. Interestingly, targeting of EphA2 for activation and subsequent downregulation with recombinant ephrin-A1 ligand was capable of normalizing keratinocyte differentiation in this human skin culture model of inflammation.…”

“…2). 18,123 This cellular localization pattern suggests that EphA receptors and ephrin-A ligands may play an important role as keratinocytes commit to a pathway of differentiation at the transition between the basal and suprabasal layers.…”

“…122 In particular, EphA2 is prominently expressed by primary keratinocytes in culture but is markedly down-regulated upon differentiation in vitro. 123 In contrast, EphA1 and EphA4 are abundantly expressed in cultured, differentiated keratinocytes and are also found in the suprabasal layers of the epidermis. Interestingly, ephrin-A1 is concentrated in the progenitor cell-containing basal layer of human epidermis (Fig.…”

“…126 Accordingly, inflammatory signals and environmental stress impact epidermal EphA2 expression as this receptor is upregulated in keratinocytes by several pro-inflammatory cytokines and ultraviolet radiation. 123,[127][128][129] Interestingly, a cluster of ephrin-A genes (EFNA1, EFNA3, EFNA4) exists on the q arm of chromosome 1 in an area proximal to the epidermal differentiation complex harboring several genes coordinately regulated during keratinization. While ephrin-A1 is a known target of tumor necrosis factor a (TNFa) signaling in many cell types, including keratinocytes, very little is known about what regulates expression of most other ephrins in the epidermis.…”

“…Thus, ephrin-A1 delivery may ultimately prove effective in resolving lesions of patients with psoriasis when combined with treatments that target inflammation. 123 EphA receptors also serve as tumor suppressors in the skin. In particular, deletion of EphA2 in mice led to significantly enhanced susceptibility to 2-stage skin carcinogenesis resulting in increased tumor size, number, and invasiveness.…”