The Exonuclease Trex2 Shapes Psoriatic Phenotype

• Published in: Journal of investigative dermatology Vol. 136; no. 12; pp. 2345 - 2355
• Main Authors: Manils, Joan, Casas, Eduard, Viña-Vilaseca, Arnau, López-Cano, Marc, Díez-Villanueva, Anna, Gómez, Diana, Marruecos, Laura, Ferran, Marta, Benito, Carmen, Perrino, Fred W., Vavouri, Tanya, de Anta, Josep Maria, Ciruela, Francisco, Soler, Concepció
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016
• Subjects: Aminoquinolines - pharmacology; Animals; Apoptosis - genetics; Biopsy, Needle; Case-Control Studies; Cell Survival - genetics; Cells, Cultured; Disease Models, Animal; Exodeoxyribonucleases - genetics; Gene Expression Regulation; Humans; Immunohistochemistry; Keratinocytes - cytology; Mice; Mice, Knockout; Phenotype; Prognosis; Psoriasis - drug therapy; Psoriasis - genetics; Psoriasis - pathology; Severity of Illness Index; Up-Regulation; IMQ; wt
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2016.05.122

Trex2 is a keratinocyte-specific 3′-deoxyribonuclease that participates in the maintenance of skin homeostasis after DNA damage. Here, we show that this exonuclease is strongly upregulated in human psoriasis, a hyperproliferative and inflammatory skin disease. Similarly, the imiquimod (IMQ)- and Il23-induced mouse psoriasis was associated with a substantial upregulation of Trex2, which was recruited into fragmented chromatin in keratinocytes that were undergoing impaired proliferation, differentiation, and cell death, indicating an important role in DNA processing. Using Trex2 knockout mice, we have found that Trex2 deficiency attenuated IMQ-induced psoriasis-like skin inflammation and enhanced IMQ-induced parakeratosis. Also, Il23-induced ear swelling was diminished in Trex2 knockout mice in comparison with wild-type (wt) mice. Transcriptome analysis identified multiple genes that were deregulated by Trex2 loss after treatment with IMQ. Specifically, immune response genes and pathways normally associated with inflammation were downregulated, whereas those related to skin differentiation and chromatin biology showed increased expression. Interestingly, Trex2 deficiency led to decreased IMQ-induced keratinocyte death via both cell autonomous and noncell autonomous mechanisms. Hence, our data indicate that Trex2 acts as a critical factor in the pathogenesis of psoriasis by promoting keratinocyte apoptosis and enucleation and thereby influencing skin immune responses.