Owing to genotyping technologies, it has been possible to identify numerous single nucleotide polymorphisms (SNPs) which contribute to pinpointing plenty of genetic markers responsible for genetic susceptibility to psoriasis, a chronic, auto-inflammatory skin disease1,2.
The genetic background of psoriasis explains uncontrolled proliferation and abnormal differentiation of keratinocytes arising from disturbances in the innate and adaptive cutaneous immune responses. The interplay between keratinocytes and immune cells, including Th1, Th17, regulatory T cells (Tregs) and neutrophils, expressed by activation of the TNFα–IL-23–Th17 proinflammatory axis, is known to cause changes in both the epidermis and dermis, i.e. epidermal hyperplasia, dermal inflammatory infiltration as well as elongation and increased permeability of blood vessels3–5.
The NOTCH signaling pathway, a highly conserved cell signaling system involving interaction between the NOTCH receptors and their ligands, has been shown to play an important role in the regulation of cell proliferation, differentiation, migration and apoptosis, and it is suggested to participate in the development of various skin diseases, including psoriasis, atopic dermatitis, hidradenitis suppurativa, Dowling Degos disease and Adams-Oliver syndrome6.
The NOTCH proteins form a family of four single-pass type 1 transmembrane receptors encoded by the NOTCH 1, 2, 3 and 4 genes. They transduce signals after activation by their transmembrane ligands, i.e. Jagged-1/-2 and Delta-like 1, 3 and 4. However, the outcome of NOTCH signaling is highly dependent on the interaction of various cellular mechanisms, especially in the context of inflammation and malignancy6,7.
Rooney et al.8 observed an upregulated Jagged-1 expression in psoriatic patients and activation of the NOTCH signaling pathway which led to hyperproliferation of the epidermal cells. Moreover, the Notch-1 receptor and its peptide ligand Delta-like 1 have been shown to regulate early keratinocytes differentiation9. Apart from its effect on the epidermal cells, NOTCH is also important in the development of the T cells and their function10. It has been proved that the NOTCH ligands are involved in polarizing the T-cell response towards producing Th1 and Th17 cells upon induction of the Delta-like ligands on the dendritic cells (DCs), however, when NOTCH interacts with the Jagged ligands, it activates production of Th2 cells10,11. This suggests that the NOTCH signals can alter the balance of the CD4 T-cell differentiation into the Th1 or Th2 lineage.
NOTCH activation is also involved in different stages of blood vessels development, including vascularization and angiogenesis12,13,14. Therefore, the NOTCH signaling pathway is supposed to play a role in psoriasis by modulation of keratinocyte proliferation, immune processes and angiogenesis.
While the role of NOTCH1 in the skin is fairly well explained, there is still little information about a possible role of NOTCH3 in the pathogenesis of skin diseases.
NOTCH3, whose transcription can be directly activated by the intracellular domain of NOTCH1, is another regulator of keratinocyte differentiation which controls involucrin expression at the late phase of the process15,16. The NOTCH3 receptor also participates in the regulation of T-cell differentiation and may be engaged in the autoinflammatory processes in psoriasis17. Therefore, our study makes an attempt to find a possible association between the NOTCH3 polymorphism and genetic susceptibility to psoriasis. One of the polymorphisms in the NOTCH3 gene (locus19p13.12) is observed in the exon 33 (6746T > C) (rs1044009) and resulted from the T (T allele) to C (C allele) substitution (GTG to GCG).
Similarly to the Notch pathway, the proteasome system, a large multiple subunit enzyme complex, also controls such processes as apoptosis, proliferation, differentiation and inflammation. PSMA6, a component of the 20S proteasome complex which is the main pathway for degradation of oxidatively damaged proteins, is coded by the gene located on the chromosome 14q13.219. There is a single PSMA6 (-8C > G) (rs1048990) nucleotide polymorphism in the exon 1 which has been found to be associated with diabetes, myocardial infarction and coronary artery disease also known as “oxidative stress conditions”20. Therefore, since psoriasis is a systemic disease, it may be surmised that the PSMA6 polymorphism plays a role in the genetic susceptibility to psoriasis.
The presence of the G allele is associated with the PSMA6 transcriptional augmentation. An increased PSMA6 activity aggravates inflammation through activation of the nuclear factor ĸB signaling pathway21. In psoriasis, activation of the nuclear factor-κB signal induces expression of keratins 6 and 16 in keratinocytes, which leads to acanthosis and shortened turnover time in the epidermis22. Both expression and activity of the 20S proteasome are also increased in the psoriatic skin cells5.
A possible genetic interplay between the SNPs of NOTCH3 (6746T > C) and PSMA6 (-8C > G) in psoriasis has not been investigated yet. Therefore, the aim of this study was to analyze the NOTCH3 (6746T > C) and PSMA6 (-8C > G) polymorphisms and the role they play in genetic susceptibility to psoriasis in the Polish psoriatic patients.