TY - JOUR
T1 - CD8+ T cells mediate RAS-induced psoriasis-like skin inflammation through IFN-γ
AU - Gunderson, Andrew J.
AU - Mohammed, Javed
AU - Horvath, Frank J.
AU - Podolsky, Michael A.
AU - Anderson, Cherie R.
AU - Glick, Adam B.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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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U2 - 10.1038/jid.2012.390
DO - 10.1038/jid.2012.390
M3 - Article
C2 - 23151849
AN - SCOPUS:84875151879
VL - 133
SP - 955
EP - 963
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 4
ER -