CD8+ T cells mediate RAS-induced psoriasis-like skin inflammation through IFN-γ

Andrew J. Gunderson, Javed Mohammed, Frank J. Horvath, Michael A. Podolsky, Cherie R. Anderson, Adam Bleier Glick

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)955-963
Number of pages9
JournalJournal of Investigative Dermatology
Volume133
Issue number4
DOIs
StatePublished - Jan 1 2013

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T-cells
Psoriasis
Keratinocytes
Skin
Inflammation
T-Lymphocytes
Interleukin-17
Nitric Oxide Synthase Type II
Th17 Cells
Th1 Cells
Pathology
Helper-Inducer T-Lymphocytes
Infiltration
Neutrophils
Chemical activation
Phenotype

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Gunderson, Andrew J. ; Mohammed, Javed ; Horvath, Frank J. ; Podolsky, Michael A. ; Anderson, Cherie R. ; Glick, Adam Bleier. / CD8+ T cells mediate RAS-induced psoriasis-like skin inflammation through IFN-γ. In: Journal of Investigative Dermatology. 2013 ; Vol. 133, No. 4. pp. 955-963.
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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.",
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Gunderson, AJ, Mohammed, J, Horvath, FJ, Podolsky, MA, Anderson, CR & Glick, AB 2013, 'CD8+ T cells mediate RAS-induced psoriasis-like skin inflammation through IFN-γ', Journal of Investigative Dermatology, vol. 133, no. 4, pp. 955-963. https://doi.org/10.1038/jid.2012.390

CD8+ T cells mediate RAS-induced psoriasis-like skin inflammation through IFN-γ. / Gunderson, Andrew J.; Mohammed, Javed; Horvath, Frank J.; Podolsky, Michael A.; Anderson, Cherie R.; Glick, Adam Bleier.

In: Journal of Investigative Dermatology, Vol. 133, No. 4, 01.01.2013, p. 955-963.

Research output: Contribution to journalArticle

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