title: CD8(+) T cells mediate RAS-induced psoriasis-like skin inflammation through IFN-γ.
abstract: The RAS signaling pathway is constitutively activated in psoriatic keratinocytes. We expressed activated H-RAS(V12G) in suprabasal keratinocytes of adult mice and observed rapid development of a psoriasis-like skin phenotype characterized by basal keratinocyte hyperproliferation, acanthosis, hyperkeratosis, intraepidermal neutrophil microabscesses, and increased T helper type 1 (Th1)/Th17 and T cell type 1 (Tc1)/Tc17 skin infiltration. The majority of skin-infiltrating CD8(+) T cells coexpressed IFN-γ and IL-17A. When RAS was expressed on a Rag1-/- background, microabscess formation, inducible nitric oxide synthase expression, and keratinocyte hyperproliferation were suppressed. Depletion of CD8(+), but not CD4(+), T cells reduced cutaneous and systemic inflammation, the RAS-induced increase in cutaneous Th17 and IL-17(+) γδ T cells, and epidermal hyperproliferation to levels similar to a Rag1-/- background. Reconstitution of Rag1-/- inducible RAS mice with purified CD8(+) T cells restored microabscess formation and epidermal hyperproliferation. Neutralization of IFN-γ, but not of IL-17A, in CD8(+) T-cell-reconstituted Rag1-/- mice expressing RAS blocked CD8-mediated skin inflammation, inducible nitric oxide synthase expression, and keratinocyte hyperproliferation. These results show that CD8(+) T cells can orchestrate skin inflammation with psoriasis-like pathology in response to constitutive RAS activation in keratinocytes, and this is primarily mediated through IFN-γ.
authors.affiliation: Pennsylvania State University, University Park, PA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gunderson
authors.forename: Javed
authors.initials: J
authors.lastname: Mohammed
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Horvath
authors.forename: Michael A
authors.initials: MA
authors.lastname: Podolsky
authors.forename: Cherie R
authors.initials: CR
authors.lastname: Anderson
authors.forename: Adam B
authors.initials: AB
authors.lastname: Glick
mesh_terms: D000038:Abscess / Q000276:immunology / Q000473:pathology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D049109:Cell Proliferation; D003872:Dermatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011565:Psoriasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D007371:Interferon-gamma; D016283:Proto-Oncogene Proteins p21(ras)