Open AccessIFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus
Author(s) -
Shuai Shao,
Lam C. Tsoi,
Mrinal K. Sarkar,
Xianying Xing,
Ke Xue,
Rattapon Uppala,
Céline C. Berthier,
Chang Zeng,
Matthew T. Patrick,
Allison C. Billi,
Joseph Fullmer,
Maria A. Beamer,
Bethany E. Perez White,
Spiro Getsios,
Andrew Schuler,
John J. Voorhees,
Sung W. Choi,
Paul W. Harms,
J. Michelle Kahlenberg,
Jóhann E. Guðjónsson
Publication year - 2019
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aav7561
Subject(s) - cytotoxicity , cell , cancer research , keratinocyte , stat1 , medicine , chemistry , immunology , interferon , in vitro , biochemistry
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.