title: The Exonuclease Trex2 Shapes Psoriatic Phenotype.
abstract: 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.
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Manils
authors.affiliation: Institute for Predictive and Personalized Medicine of Cancer (IMPPC), Can Ruti Campus, Badalona, Barcelona, Spain; Josep Carreras Leukaemia Research Institute, Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Casas
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Viña-Vilaseca
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; IDIBELL and Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: López-Cano
authors.affiliation: Institute for Predictive and Personalized Medicine of Cancer (IMPPC), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Díez-Villanueva
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Gómez
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Marruecos
authors.affiliation: Department of Dermatology, Hospital del Mar, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ferran
authors.affiliation: Protecció Radiològica, Centres Científics i Tecnològics, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Benito
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Fred W
authors.initials: FW
authors.lastname: Perrino
authors.affiliation: Institute for Predictive and Personalized Medicine of Cancer (IMPPC), Can Ruti Campus, Badalona, Barcelona, Spain; Josep Carreras Leukaemia Research Institute, Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Tanya
authors.initials: T
authors.lastname: Vavouri
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: de Anta
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; IDIBELL and Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: concepciosoler@ub.edu.
authors.forename: Concepció
authors.initials: C
authors.lastname: Soler
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D000077271:Imiquimod; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011379:Prognosis; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index; D015854:Up-Regulation
chemical_list: D000634:Aminoquinolines; D005090:Exodeoxyribonucleases; C540589:Trex2 protein, mouse; D000077271:Imiquimod