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Translation-dependent skin hyperplasia is promoted by type 1/17 inflammation in psoriasis

Background: Psoriasis vulgaris (PV) is a chronic skin inflammatory disease and characterized by aberrant epidermal hyperplasia. The molecule eukaryotic initiation factor (eIF) 4E controls translation initiation of certain protein synthesis and determines cell cycle or differentiation fate.

Objective: To determine the role of eIF4E in keratinocytes abnormal differentiation in the context of psoriasis.

Methods: The expression of eIF4E in psoriatic skin lesions and normal skin from human subjects was examined by western blot and immunohistochemistry. In a murine model of psoriasis-like dermatitis that is induced by topical imiquimod, 4EGI-1 was used to inhibit eIF4E activities. To measure murine skin eIF4E and keratinocytes differentiation, immunofluorescence and western blot assays were conducted. Normal human epidermal keratinocytes (NHEK) were isolated, cultured, and stimulated with cytokines including TNF-α, IFN-γ, and IL-17A, respectively. Immunofluorescence and western blot were performed to test eIF4E and effect of 4EGI-1 in a co-culture system.

Results: Compared with healthy controls, skin lesions from patients with PV exhibited a higher expression of eIF4E, which was positively correlated with the epidermal thickness. This expression pattern of eIF4E was replicated by the imiquimod-induced murine model. Skin hyperplasia and eIF4E activities in the murine model were attenuated by the administration of 4EGI-1. Both IFN-γ and IL-17A, rather than TNF-α, are sufficient to induce NHEK abnormal differentiation. This effect can be disrupted by 4EGI-1.

Conclusion: eIF4E plays a crucial role in keratinocytes abnormal differentiation driven by type 1/17 inflammation in the context of psoriasis. The initiation of abnormal translation provides an alternative treatment target for psoriasis.

 

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Title: The Role of eIF4E in Abnormal Keratinocyte Differentiation in Psoriasis

Abstract: Psoriasis vulgaris (PV) is a chronic inflammatory skin disorder characterized by aberrant epidermal hyperplasia and keratinocyte differentiation. This study aimed to investigate the involvement of eukaryotic initiation factor 4E (eIF4E) in the abnormal differentiation of keratinocytes in the context of psoriasis. The expression of eIF4E was analyzed in psoriatic skin lesions and normal skin samples using western blot and immunohistochemistry. A murine model of psoriasis-like dermatitis was induced using topical imiquimod, and eIF4E activity was inhibited using 4EGI-1. Immunofluorescence and western blot assays were employed to evaluate eIF4E expression and keratinocyte differentiation in murine skin. Normal human epidermal keratinocytes (NHEK) were stimulated with cytokines (TNF-α, IFN-γ, and IL-17A) in a co-culture system, and the effects of eIF4E inhibition were assessed.

The results demonstrated that eIF4E expression was significantly elevated in skin lesions from PV patients compared to healthy controls, and its expression positively correlated with epidermal thickness. Similar results were observed in the imiquimod-induced murine model. Administration of 4EGI-1 attenuated skin hyperplasia and eIF4E activity in the murine model. Furthermore, stimulation of NHEK with IFN-γ and IL-17A, but not TNF-α, induced abnormal keratinocyte differentiation, which was effectively disrupted by 4EGI-1 treatment.

These findings suggest that eIF4E plays a critical role in the abnormal differentiation of keratinocytes driven by type 1/17 inflammation in psoriasis. The dysregulated translation initiation mediated by eIF4E provides a potential target for alternative treatment strategies in psoriasis.

Keywords: Psoriasis vulgaris, eukaryotic initiation factor 4E, keratinocytes, abnormal differentiation, inflammation, 4EGI-1.

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