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

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.

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis—Translation of Pathogenic Fundamentals Into an In Vitro Model

“…Specifically, it is predominantly produced by natural killer cells, group 1 innate lymphoid cells, yδ T cells and CD8+ cytotoxic T cells as well as CD4+ Th1 cells [as reviewed in ( 124 )]. Its receptor (IFNyR) signals via the JAK1/JAK2 and STAT1/STAT2 pathway ( 107 , 125 ). Shao et al.…”

“…Stimulation with eNA results in a pronounced expression of typical ID-associated cytokines within different keratinocyte models. IFNy, mainly produced by lymphocytes, is known to play a pivotal role in the pathogenesis of diseases featuring ID ( 107 – 109 ), and has been shown to induce typical morphological changes in human epidermis equivalents, in vitro ( 110 ). Herein, we aim to deliver an in-depth analysis of differentially regulated genes in our ID model and furthermore present synergistic effects of endogenous nucleic acids in addition to IFNy on human keratinocytes.…”

Emerging Topical and Systemic JAK Inhibitors in Dermatology

“…Treatment of LP is mainly based on oral or topical glucocorticosteroids, phototherapy, retinoids or immunosuppressive drugs such as cyclosporine or methotrexate (107). There is growing evidence that LP is a Th1 driven disease (10, 108, 109), although Th17-associated cytokines have also been reported in LP (110–112). A recent study showed that the T cell infiltrate presents high numbers of Th1/Tbet + cells and the presence of IL-17A + cells, disposed beneath the basal cells of the epidermis (10).…”

Extracellular vesicles in Inflammatory Skin Disorders: from Pathophysiology to Treatment

“…LP is the third most common inflammatory skin disease, characterized by epidermal keratinocyte death and dense infiltration of T cells in the dermis 173 . We previously provided evidence of the role of IFN-γ in the cell-mediated cytotoxicity of keratinocytes in LP 174 . Recently, several studies explored the function of EVs in LP.…”