title: Macrophage-mediated psoriasis can be suppressed by regulatory T lymphocytes.
abstract: We recently described an inducible human TNF transgenic mouse line (ihTNFtg) that develops psoriasis-like arthritis after doxycycline stimulation and analysed the pathogenesis of arthritis in detail. Here, we show that the skin phenotype of these mice is characterized by hyperproliferation and aberrant activation of keratinocytes, induction of pro-inflammatory cytokines, and infiltration with Th1 and Treg lymphocytes, particularly with macrophage infiltration into lesional skin, thus pointing to a psoriasis-like phenotype. To reveal the contribution of T cells and macrophages to the development of TNF-mediated psoriasis, ihTNFtg mice were crossbred into RAG1KOmice lacking mature T and B cells. Surprisingly, the psoriatic phenotype in the double mutants was not reduced; rather, it was enhanced. The skin showed significantly increased inflammation and in particular, increased infiltration by macrophages. Consequently, depletion of macrophages in RAG1KOor wild-type mice led to decreased disease severity. On the contrary, depletion of Treg cells in wild-type mice increased both psoriasis and the number of infiltrating macrophages, while adoptive transfer of Foxp3-positive cells into RAG1KOor wild-type mice decreased both the development of psoriasis and macrophage infiltration. Thus, we conclude that Treg lymphocytes inhibit the pro-inflammatory activity of macrophages, which are the major immune effector cells in hTNF-mediated psoriasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Institute of Molecular Virology, ZMBE, University Hospital Muenster, 48149, Muenster, Germany.
authors.forename: Rafael
authors.initials: R
authors.lastname: Leite Dantas
authors.affiliation: Institute of Molecular Virology, ZMBE, University Hospital Muenster, 48149, Muenster, Germany.
authors.forename: Dörthe
authors.initials: D
authors.lastname: Masemann
authors.affiliation: Institute of Molecular Virology, ZMBE, University Hospital Muenster, 48149, Muenster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schied
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, 50931, Cologne, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Bergmeier
authors.affiliation: Institute of Immunology, University Hospital Muenster, 48149, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Institute of Dermatology, University Hospital Muenster, 48149, Muenster, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Loser
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, 50931, Cologne, Germany.|Department of Pediatrics and Adolescent Medicine, University Hospital of Cologne, 50931, Cologne, Germany.
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
authors.affiliation: Department of Pediatrics, Rheumatology and Immunology, University Hospital Muenster, 48149, Muenster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.affiliation: Institute of Molecular Virology, ZMBE, University Hospital Muenster, 48149, Muenster, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.affiliation: Institute of Molecular Virology, ZMBE, University Hospital Muenster, 48149, Muenster, Germany. vwixler@uni-muenster.de.
authors.forename: Viktor
authors.initials: V
authors.lastname: Wixler
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060833:Cellular Microenvironment; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D015603:Keratinocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology; D012867:Skin / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein
keywords: T regulatory cells; TNFα-mediated psoriasis; doxycycline-inducible human TNFα-transgenic mouse; skin macrophages