Studies on Vitamin A Signaling in Psoriasis : A Comparison Between Normal and Lesional Keratinocytes

Abstract: Vitamin A and metabolites (retinoids) are crucial for normal epidermal maturation. Physiological effects are mediated by retinoic acid (RA) that activates nuclear retinoic acid receptors (RARs) in complexes with retinoid X receptors (RXRs), resulting in altered gene transcription.Psoriasis is a common disease with unknown etiology. Lesions display inflammation, hyperproliferation, and disturbed epidermal maturation. Treatments include topical or oral synthetic retinoids that allegedly bind to and activate the RARs.The mRNA expression of retinoid receptors RARα/γ and RXRα was studied in normal and psoriatic skin samples. RARα and RXRα were significantly reduced in psoriatic plaques as compared to non-lesional and normal skin. In situ immunofluorescence detection revealed altered distribution patterns of the receptor proteins in lesional skin. All three receptor proteins were more intensely detected in the lower half of the epidermis but were significantly reduced in the superficial epidermis compared to both normal and non-lesional skin. In order to evaluate the retinoid signaling system in psoriatic lesions, we compared the effect of topical RA on the expression of the cellular RA-binding protein II (CRABPII) in psoriatic and normal skin. CRABPII was induced by RA on mRNA and protein level in non-lesional and normal skin but not in lesional skin, where the basal expression of CRABPII was already up-regulated.Changes in retinoid signaling during keratinocyte differentiation in vitro were studied by measuring retinoid receptor and RAR-ligand levels. Exposure to differentiation-inducing levels of calcium, phorbol myristate acetate (PMA) or interferon-γ (IFNγ) led to increased RAR-ligand levels but PMA and IFNγ caused receptor protein loss due to increased proteasomal degradation. Since an increased IFNγ level is a hallmark of psoriatic inflammation, this might be a cause of altered retinoid signaling in lesional epidermis.Conclusion: Keratinocyte differentiation is accompanied by alterations in the retinoid signaling system. In psoriatic lesions, this system appears to be dysfunctioning due to reduced retinoid receptor levels, which might be an important event in the pathogenesis of the disease.