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.
Bibliographical noteFunding Information:
We thank the staff of the Microscopy and Cytometry Facility of the Huck Institutes of the Life Sciences for assisting with flow cytometry and tissue histology, and Shailaja Hegde for her assistance with adoptive lymphocyte transfer studies. Grant Support: ABG was supported by National Cancer Institute CA117597 and National Psoriasis Foundation. AJG was supported through fellowship awards from Bristol Myers Squibb and The College of Agricultural Sciences, The Pennsylvania State University.