The Exonuclease Trex2 Shapes Psoriatic Phenotype

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 Il2...

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Published inJournal 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
LanguageEnglish
Published United States Elsevier Inc 01.12.2016
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Summary: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.
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ISSN:0022-202X
1523-1747
DOI:10.1016/j.jid.2016.05.122