A study published in the Journal of Investigative Dermatology has identified a potential therapeutic target for the treatment of psoriasis, a chronic inflammatory skin disease that affects up to 2% of the population and has no cure yet. The study shows that the TREX2 gene plays an important role in the inflammatory response that develops during the disease. The research, conducted by researchers of the Department of Pathology and Experimental Therapies of the Faculty of Medicine and Health Sciences of the University of Barcelona and of the Bellvitge Biomedical Research Institute (IDIBELL), contributes to increase the knowledge of this complex and multi-faceted inflammatory factor disease and opens the door to the development of new therapeutic strategies. The TREX2 gene encodes an enzyme related to the maintenance of genomic stability and some repair mechanisms such as DNA degradation. In previous studies, the research team saw that this protein constituted a specific presence on the skin. Furthermore, the study of the phenotype of deficient mice for this protein shows that the loss of TREX2 creates a greater susceptibility to skin carcinogenesis induced by UV rays.
Skin injuries, infections, chemicals, and other cell stressors can prime psoriasis onset, linking the release of DNA during keratinocyte death to the development of disease pathogenesis. Indeed, cytosolic DNA in keratinocytes and extracellular DNA associated with neutrophil extracellular traps (NETs) are found in psoriatic skin but are not detected in healthy skin. It is of note that nucleases are implicated in the free nucleic acid degradation and these have been involved in inflammatory diseases. To go further in the role of TREX2 in homeostasis and skin pathogenesis, researchers wanted to see the role of these enzymes on psoriasis. At the beginning, they analyzed several biopsies of patients and people without the disease. Later, using different models of psoriasis mice, they compared the evolution of the disease on normal and deficient mice of TREX2 to infer the function of this molecule. “The results show that TREX2 would play an important role in the degradation of DNA on the epidermis of psoriasis, causing the characteristic inflammatory response of this disease,” says Concepció Soler, head of the study and professor at the Department of Pathology and Experimental Therapies of the University of Barcelona. The study shows that the skin with psoriasis has a high increase in TREX2 expression that focuses on the cell nucleus of keratinocytes – the most abundant cells on the skin – that are spreading, dying and differentiating strangely. Therefore, the results suggest an important role of the TREX2 gene in DNA stability.
Expression data indicate that the exonuclease TREX2 seems to be the only DNase that is strongly upregulated in psoriasis. The multifunctional endonuclease APE1, which is involved in both DNA repair and redox signaling, has been shown to be moderately upregulated in psoriasis, where it acts as an intrinsic modulator of keratinocyte inflammatory responsesJoan Manils, first author of the study and a member of the aforementioned department at the Trinity Biomedical Sciences Institute of Ireland explains: “In our study, we highlighted the essential role of TREX2 to promote DNA degradation and subsequent cell death of keratinocytes, influencing the immune response of the skin. The release of different signals from dying skin cells contributes to the creation and spread of chronic immune cells. These trigger a chronic inflammatory response and irregular skin differentiation. “In a separate set of experiments, the authors also tested how genetically eliminating the TREX2 and DN1L2 genes, with similar functions, tongue keratinocytes accumulate DNA but does not trigger any Inflammatory response: this proves that the two genes cooperate in DNA degradation during lingual keratinocyte maturation. The retention of aberrant DNA is tolerated in the oral mucosa, which may explain why psoriasis never attacks the internal mucosa as they do, however, diseases like Crohn’s disease.
The team results show TREX2 as a potential therapeutic target for addressing this disease with a different and more focused strategy. The next objective of the researchers is to decode the mechanism of action of TREX2 in the development and maintenance of psoriasis, so as to design an exclusive therapeutic strategy for the treatment of this disease
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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