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.

Neutrophils have a pathogenic function in inflammation via releasing pro-inflammatory mediators or neutrophil extracellular traps (NETs). However, their heterogeneity and pro-inflammatory mechanisms remain unclear. Here, we demonstrate that CXCR4^hi neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4^lo neutrophils, CXCR4^hi neutrophils have enhanced NETs formation, phagocytic function, neutrophil degranulation, and overexpression of pro-inflammatory cytokines and chemokines in vitro. This is accompanied by a metabolic shift in CXCR4^hi neutrophils toward glycolysis and lactate release, thereby promoting vascular permeability and remodeling. CXCR4 expression in neutrophils is dependent on CREB1, a transcription factor activated by TNF and CXCL12, and regulated by de novo synthesis. In vivo, CXCR4^hi neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4^hi neutrophils through CXCR4 or CXCL12 inhibition leads to suppression of immune responses. In this work, our study identifies CREB1 as a critical regulator of CXCR4^hi neutrophil development and characterizes the contribution of CXCR4^hi neutrophils to vascular remodeling and inflammatory responses in skin.

Circulating exosomal miR-375-3p promotes keratinocyte apoptosis via XIAP repression in Stevens-Johnson syndrome and toxic epidermal necrolysis.

Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is “autoimmunity prone,” showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cell–activating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-κ, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity.

Altered epidermal differentiation along with increased keratinocyte proliferation is a characteristic feature of psoriasis and pityriasis rubra pilaris (PRP). However, despite this large degree of overlapping clinical and histologic features, the molecular signatures these skin disorders share are unknown. Using global transcriptomic profiling, we demonstrate that plaque psoriasis and PRP skin lesions have high overlap, with all differentially expressed genes in PRP relative to normal skin having complete overlap with those in psoriasis. The major common pathway shared between psoriasis and PRP involves the phospholipases PLA2G2F, PLA2G4D, and PLA2G4E, which were found to be primarily expressed in the epidermis. Gene silencing each of the 3 PLA2s led to reduction in immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their proinflammatory roles. Lipidomic analyses demonstrated that PLA2s affect mobilization of a phospholipid-eicosanoid pool, which is altered in psoriatic lesions and functions to promote immune responses in keratinocytes. Taken together, our results highlight the important role of PLA2s as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential therapeutic targets for both diseases.