title: Trim32 Deficiency Enhances Th2 Immunity and Predisposes to Features of Atopic Dermatitis.
abstract: Altered innate immunity is a feature of certain skin inflammatory diseases such as psoriasis and atopic dermatitis (AD). In this study, we provide evidence that deficiency in Trim32 (a tripartite motif [TRIM] protein with innate antiviral activity) contributes to a T helper type 2 biased response and predisposes to features of AD in mice. On treatment with the toll-like receptor 7 agonist imquimod (IMQ), Trim32 knockout mice displayed compromised psoriasiform phenotypes and defective T helper type 17 response. Instead, IMQ treatment of Trim32 knockout mice induced AD-like phenotypes with enhanced skin infiltration of eosinophils and mast cells, elevation of T helper type 2 cytokines/chemokines expression, and reduced expression of filaggrin protein expression. Furthermore, although the induction of phosphorylated Stat3 and RelA was compromised after IMQ treatment in the knockout mice, phosphorylated Stat6 was elevated. CC chemokine ligand 20 induction by tumor necrosis factor-α and IL-17A was reduced in Trim32-deficient keratinocytes, whereas CC chemokine ligand 5 induction by tumor necrosis factor-α and IL-4 was enhanced. In addition, Trim32 protein levels were elevated in mice treated with IMQ. Unlike Trim32 overexpression in psoriasis, TRIM32 levels were low in patients with AD. Based on Trim32 induction by IMQ, the lower levels of TRIM32 in AD skin compared with healthy control and psoriatic skin suggest a defective TRIM32 pathway in AD pathogenesis.
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA. Electronic address: liuy@ohsu.edu.
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: De La Torre
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Barling
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsujikawa
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Hornick
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Hanifin
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Simpson
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Swanzey
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Wortham
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Coussens
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, Oregon, USA; Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon, USA. Electronic address: kuleszma@ohsu.edu.
authors.forename: Molly
authors.initials: M
authors.lastname: Kulesz-Martin
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D018946:Chemokine CCL5 / Q000032:analysis; D003876:Dermatitis, Atopic / Q000209:etiology* / Q000276:immunology; D000091344:Filaggrin Proteins; D000077271:Imiquimod; D007381:Intermediate Filament Proteins / Q000032:analysis; D008407:Mast Cells / Q000502:physiology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D050800:STAT6 Transcription Factor / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000502:physiology
chemical_list: D000634:Aminoquinolines; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000077271:Imiquimod