IFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus

Shuai Shao, Lam C. Tsoi, Mrinal K. Sarkar, Xianying Xing, Ke Xue, Ranjitha Uppala, Celine C. Berthier, Chang Zeng, Matthew Patrick, Allison C. Billi, Joseph Fullmer, Maria A. Beamer, Bethany Perez-White, Spiro Getsios, Andrew Schuler, John J. Voorhees, Sung Choi, Paul Harms, J. Michelle Kahlenberg, Johann E. Gudjonsson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to CD8+ T cell-mediated cytotoxic responses through MHC class I induction in a coculture model. We show that this process is dependent on Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1), but not JAK1 or STAT2 signaling. Last, using drug prediction algorithms, we identify JAK inhibitors as promising therapeutic agents in LP and demonstrate that the JAK1/2 inhibitor baricitinib fully protects keratinocytes against cell-mediated cytotoxic responses in vitro. In summary, this work elucidates the role and mechanisms of IFN-γ in LP pathogenesis and provides evidence for the therapeutic use of JAK inhibitors to limit cell-mediated cytotoxicity in patients with LP.

Original languageEnglish (US)
Article numbereaav7561
JournalScience translational medicine
Volume11
Issue number511
DOIs
StatePublished - Sep 25 2019

ASJC Scopus subject areas

  • Medicine(all)

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