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Published on: September 27, 2015
Inhibition of eukaryotic translation initiation factor 1 A (eIF1A) and 3B (eIF3B) diminishes the psoriatic phenotype
Nicole Golob-Schwarzl1, Natalie Bordag1, Nitesh Shirsath1
1Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
Background:
Psoriasis is a systemic inflammatory skin disease for which new topical treatments are needed. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which regulate gene expression in processes such as proliferation, apoptosis, and differentiation. However, their role in psoriasis remains unclear.
Objective:
To investigate the contribution of eIF1A and eIF3B to psoriasis pathogenesis and evaluate the therapeutic potential of their inhibition via small interfering RNA (siRNA).
Methods:
We used two mouse models reflecting different mechanisms of psoriasis: (i) topical application of imiquimod (IMQ) and (ii) K5.TGFβ transgenic mice promoting keratinocyte proliferation. eIF1A and eIF3B were inhibited by either topical or systemic siRNA administration. A 3D human psoriasis model was also used for validation.
Results:
Inhibition of eIF1A and eIF3B reduced inflammation in both mouse models and the 3D human model. Downregulation of these factors normalized keratinocyte proliferation, epidermal thickness, and cytokine expression (e.g., TNFα, IL-1β, IL-17, IL-22). Differentiation markers such as KRT16 and FLG were restored. These findings suggest that eIF1A and eIF3B play a key role in maintaining the psoriatic inflammatory phenotype.
Conclusion:
Our findings reveal a translational imbalance in psoriasis and identify eIF1A and eIF3B as crucial regulators of disease pathophysiology. Targeting these factors represents a promising new therapeutic strategy for psoriasis treatment.
Insights
Targeting eukaryotic translation initiation factors (eIFs) like eIF1A and eIF3B offers a new therapeutic approach for psoriasis. Inhibiting these factors reduced inflammation and normalized skin cell behavior in preclinical models.
Area of Science:
- Dermatology and Molecular Biology
- Inflammation and Immunology
Background:
- Psoriasis is a chronic inflammatory skin condition requiring novel treatments.
- Overexpression of eukaryotic translation initiation factors (eIFs) is observed in psoriatic inflammation, but their specific role is unknown.
Purpose of the Study:
- To investigate the role of eIF1A and eIF3B in psoriasis development.
- To evaluate the therapeutic potential of inhibiting eIF1A and eIF3B using small interfering RNA (siRNA).
Main Methods:
- Utilized imiquimod (IMQ)-induced and K5.TGFβ transgenic mouse models of psoriasis.
- Administered topical or systemic siRNA targeting eIF1A and eIF3B.
- Validated findings in a 3D human psoriasis model.
Main Results:
- Inhibition of eIF1A and eIF3B significantly reduced inflammation in both mouse models and the human 3D model.
- Downregulation of eIF1A and eIF3B normalized keratinocyte proliferation, epidermal thickness, and key inflammatory cytokine levels.
- Restoration of differentiation markers (KRT16, FLG) was observed, indicating a reversal of the psoriatic phenotype.
Conclusions:
- eIF1A and eIF3B are critical regulators of psoriatic inflammation and disease pathophysiology.
- Targeting eIF1A and eIF3B with siRNA presents a promising therapeutic strategy for psoriasis.
- Findings highlight a translational imbalance contributing to psoriasis pathogenesis.
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