Inhibition of eukaryotic translation initiation factor 1A (eIF1A) and 3B (eIF3B) diminishes the psoriatic phenotype in two mouse models and human 3D model samples
BackgroundPsoriasis is a systemic inflammatory disease for which new topical treatments are required. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which critically regulate gene expression in many important cellular processes, including proliferation, apoptosis, and differentiation. However, the exact link between overexpression of eIF and psoriasis is unknown. Here, we investigated the role of eIFs, particularly eIF1A and eIF3B, and the impact of their inhibition on the pathophysiology of psoriasis. MethodsWe used two mouse models reflecting the pathophysiology of psoriasis: (i) BALB/c mice topically treated with the immune activator imiquimod (IMQ) and (ii) K5.TGF{beta} transgenic mice. eIF1A and eIF3B were inhibited by either topical or systemic application of specific small interfering RNA (siRNA). In addition, we employed commercial human 3D psoriatic skin model samples. Importantly, in situ mRNA detection-based padlock probes against transcript variants of eIF1A und eIF3B was performed. ResultsTopical and systemic inhibition of eIF1A and eIF3B inhibited inflammation in both imiquimod and TGF{beta} mouse models as well as in a human 3D psoriasis model. Downregulation of eIF1A and eIF3B was associated with normalization of cell proliferation, restoration of the inflammatory milieu and epidermal hyperplasia of psoriasis, and normalization of levels of proinflammatory cytokines (e.g., TNF, IL-1b, IL-17, and IL-22) and keratinocyte differentiation markers (e.g., KRT16 and FLG). ConclusionThese results reveal an imbalance in translation and emphasize the crucial role of eIF1A and eIF3B in the pathophysiology of psoriasis. Targeting eIFs opens new avenues for the development of novel therapeutic treatment strategies against psoriasis.