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Effect of keratinocyte-intrinsic VISTA deletion on UV-induced type I interferon and inflammatory gene expression in mouse epidermis [bulk RNA-seq]

ABSTRACT: (abstract)Type I interferon (IFN-I) signaling is a central driver of cutaneous lupus erythematosus (CLE), but the keratinocyte-intrinsic checkpoints that restrain UV-triggered IFN-I responses remain poorly defined. Here we report that the immune checkpoint VISTA (encoded by Vsir) is expressed in epidermal keratinocytes and acts cell-intrinsically to suppress cGAS–STING–dependent IFN-I induction following ultraviolet (UV) exposure. Conditional deletion of Vsir in keratinocytes (K14Cre-Vsir^fl/fl^) results in markedly elevated expression of interferon-stimulated genes (ISGs), chemokines, and antigen presentation machinery at baseline and is further amplified by acute UVB irradiation. Co-deletion of STING (Sting1) abrogates this hyperinflammatory transcriptional program, placing VISTA upstream of the cGAS–STING–IFN-I axis. Mechanistically, our data support a model in which VISTA restrains EGFR/LRIG1/NUMB-dependent stabilization of phosphorylated (pY245) STING, thereby tuning the magnitude of UV-induced IFN-I output. These findings identify a keratinocyte-intrinsic role for VISTA in suppressing sterile cutaneous inflammation and have translational relevance for photosensitive autoimmune skin disease and for cutaneous immune-related adverse events of VISTA-targeted therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE335221 | GEO | 2026/06/16

REPOSITORIES: GEO

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	GSE335221_featurecounts.readcounts.ann.tsv.gz	Tabular
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Effect of keratinocyte-intrinsic VISTA deletion on UV-induced type I interferon and inflammatory gene expression in mouse epidermis [scRNA-seq]

Project description:Type I interferon (IFN-I) signaling is a central driver of cutaneous lupus erythematosus (CLE), but the keratinocyte-intrinsic checkpoints that restrain UV-triggered IFN-I responses remain poorly defined. Here we report that the immune checkpoint VISTA (encoded by Vsir) is expressed in epidermal keratinocytes and acts cell-intrinsically to suppress cGAS–STING–dependent IFN-I induction following ultraviolet (UV) exposure. Conditional deletion of Vsir in keratinocytes (K14Cre-Vsir^fl/fl^) results in markedly elevated expression of interferon-stimulated genes (ISGs), chemokines, and antigen presentation machinery at baseline and is further amplified by acute UVB irradiation. Co-deletion of STING (Sting1) abrogates this hyperinflammatory transcriptional program, placing VISTA upstream of the cGAS–STING–IFN-I axis. Mechanistically, our data support a model in which VISTA restrains EGFR/LRIG1/NUMB-dependent stabilization of phosphorylated (pY245) STING, thereby tuning the magnitude of UV-induced IFN-I output. These findings identify a keratinocyte-intrinsic role for VISTA in suppressing sterile cutaneous inflammation and have translational relevance for photosensitive autoimmune skin disease and for cutaneous immune-related adverse events of VISTA-targeted therapies.

2026-06-16 | GSE335307 | GEO

Primary Keratinocyte Model of Actinic Keratosis Reveals UV-Induced DNA Damage Accumulation and Persistent Interferon Signaling

Project description:Actinic keratosis (AK) is a precancerous, UV-induced skin lesion that can progress to cutaneous squamous cell carcinoma (cSCC). While UV radiation is known to drive mutations and immunosuppression in the skin, keratinocyte-intrinsic responses to chronic, low-dose solar UV exposure have been insufficiently studied in AK. We established a patient-derived in vitro model using primary keratinocytes from AK lesions and age-matched, sun-exposed skin to investigate how repeated low-dose UV irradiation shapes keratinocyte stress responses. Integrating high-content morphological profiling, cyclobutane pyrimidine dimer (CPD) quantification and bulk RNA sequencing, we observed pronounced morphological remodeling and persistent DNA damage in AK keratinocytes despite activation of DNA repair and unfolded protein response pathways. Transcriptomic analyses revealed constitutive and UV-enhanced interferon signaling in AK cells, including upregulation of innate DNA sensing and ISGylation genes. Meta-analysis of five independent datasets confirmed interferon pathway activation as a conserved feature of AK, and IFN-α exposure further sensitized AK keratinocytes to UV-induced CPD formation. Our primary model thus uncovers sustained interferon signaling and attenuated DNA damage repair as key keratinocyte-intrinsic features of AK, suggesting that chronic interferon responses may modulate UV-induced damage and contribute to early photocarcinogenic processes.

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Cortistatin antagonizes Piezo1-STING axis and facilitates mitochondrial homeostasis of keratinocytes by attenuating AGEs accumulation in diabetic ulcers [RNA-Seq IFN1]

Project description:Diabetic complications frequently arise in mechanically stressed regions, yet the molecular links between biomechanical forces and metabolic dysfunction remain unclear. Here, we demonstrate that mechanical stress induces glucose accumulation and downstream metabolic stress in keratinocytes, leading to mitochondrial injury and inflammation. Mechanistically, Piezo1 activation led to intracellular glucose overload and excessive advanced glycation end-products (AGEs) accumulation, which induced mitochondrial DNA (mtDNA) leakage into the cytosol and subsequently activated the cGAS–STINGsignaling cascade. Keratinocyte-specific Piezo1 deletion markedly reduced AGEs accumulation and preserved mitochondrial integrity, while Stimulator of interferon genes (STING) ablation reproduced similar downstream protective effects. Keratinocyte-specific deletion of the mechanosensor Piezo1 reduces advanced glycation end-products (AGEs) accumulation, preserves mitochondrial integrity, and dampens inflammatory signaling. Further, we show that this injury cascade involves cytosolic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS–STING pathway. Stimulator of interferon genes (STING) ablation recapitulates the protective phenotype, confirming its downstream role. Notably, we identify Cortistatin (CST), an endogenous neuropeptide, as a previously unrecognized inhibitory ligand of Piezo1. CST binding attenuates calcium intake and glucose accumulation under mechanical stress, conferring notable protection in vitro and in diabetic ulcer (DUs) models. These findings uncover a CST–Piezo1–STING regulatory axis that integrates mechanical and metabolic cues to drive keratinocyte dysfunction in diabetes.

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Cortistatin antagonizes Piezo1-STING axis and facilitates mitochondrial homeostasis of keratinocytes by attenuating AGEs accumulation in diabetic ulcers

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Transcriptional changes in murine keratinocyte harbouring heterozygous or homozygous R245W p53 mutation in vitro

Project description:Human epidermis is colonized by clones carrying UV light induced p53 mutations, thought to be the origin of keratinocyte derived cancers, but the cellular mechanisms underlying the formation of these clones are not well understood. To address this we generated a new conditional knock-in mouse model bearing one of the hot spot mutations, R245W (R248W in human), targeted to the p53 locus, with its expression linked to a GFP reporter to enable lineage tracing. This mutation is one of the most frequently observed in cutaneous squamous cell carcinomas. We find that when induced in individual epidermal interfollicular progenitor cells the p53 mutant cells are dominant over wild type keratinocytes expanding to colonize the majority of the interfollicular epidermis. This process is accelerated by sub erythema doses ultraviolet light exposure. In vitro analysis of the trancriptomes can explain the intrinsic function driving clonal expansion.

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STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity

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