Photosensitivity and c-GAS-dependent type I IFN activation in lupus patients with TREX1 deficiency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA715774 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14016224.fastq.gz | Fastqsanger.gz | |||
| SRR14016225.fastq.gz | Fastqsanger.gz | |||
| SRR14016226.fastq.gz | Fastqsanger.gz | |||
| SRR14016227.fastq.gz | Fastqsanger.gz | |||
| SRR14016228.fastq.gz | Fastqsanger.gz |
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Project description:The autoimmune disease lupus erythematosus (lupus) is characterized in part by photosensitivity, where patients can develop inflammatory skin lesions with even ambient ultraviolet radiation (UVR) exposure. Evidence points to a role for type I interferon (IFN-I) in photosensitivity, but mechanistic understanding remains limited. We have shown that photosensitivity in lupus models is at least in part attributable to Langerhans cell (LC) dysfunction. Healthy LCs limit photosensitivity via a disintegrin and metalloprotease 17 (ADAM17), a sheddase that normally limits UVR-induced skin inflammation by releasing soluble epidermal growth factor receptor (EGFR) ligands to support keratinocyte survival. On the other hand, LCs from lesional and even non-lesional lupus model skin show reduced ADAM17 activity and mRNA expression. Non-lesional human lupus skin also showed evidence of LC dysfunction, and, here, we asked how the lupus skin environment contributes to this dysfunction. We show that non-lesional skin in human CLE and multiple photosensitive lupus models share gene expression patterns consistent with a high IFN environment and LC dysfunction. IFN-I inhibits murine and human LC ADAM17 activity, and anti-IFNAR1 in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) are a mediator of ADAM17 activity, and we show that lupus models have reduced UVR-induced LC ROS generation that is restored by anti-IFNAR1. Our findings suggest shared pathogenic mechanisms of photosensitivity in human and murine lupus skin and a model whereby the IFN-I-rich microenvironment in non-lesional lupus skin inhibits UVR-induced ADAM17 activity, predisposing to photosensitivity. Our data also suggest that the beneficial effects of the recently FDA-approved anifrolumab (anti-IFNAR1) on human lupus skin could act in part by restoring LC function.
2024-02-23 | GSE255519 | GEO
Project description:The autoimmune disease lupus erythematosus (lupus) is characterized in part by photosensitivity, where patients can develop inflammatory skin lesions with even ambient ultraviolet radiation (UVR) exposure. Evidence points to a role for type I interferon (IFN-I) in photosensitivity, but mechanistic understanding remains limited. We have shown that photosensitivity in lupus models is at least in part attributable to Langerhans cell (LC) dysfunction. Healthy LCs limit photosensitivity via a disintegrin and metalloprotease 17 (ADAM17), a sheddase that normally limits UVR-induced skin inflammation by releasing soluble epidermal growth factor receptor (EGFR) ligands to support keratinocyte survival. On the other hand, LCs from lesional and even non-lesional lupus model skin show reduced ADAM17 activity and mRNA expression. Non-lesional human lupus skin also showed evidence of LC dysfunction, and, here, we asked how the lupus skin environment contributes to this dysfunction. We show that non-lesional skin in human CLE and multiple photosensitive lupus models share gene expression patterns consistent with a high IFN environment and LC dysfunction. IFN-I inhibits murine and human LC ADAM17 activity, and anti-IFNAR1 in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) are a mediator of ADAM17 activity, and we show that lupus models have reduced UVR-induced LC ROS generation that is restored by anti-IFNAR1. Our findings suggest shared pathogenic mechanisms of photosensitivity in human and murine lupus skin and a model whereby the IFN-I-rich microenvironment in non-lesional lupus skin inhibits UVR-induced ADAM17 activity, predisposing to photosensitivity. Our data also suggest that the beneficial effects of the recently FDA-approved anifrolumab (anti-IFNAR1) on human lupus skin could act in part by restoring LC function.
2024-01-10 | GSE222573 | GEO
Project description:The autoimmune disease lupus erythematosus (lupus) is characterized in part by photosensitivity, where patients can develop inflammatory skin lesions with even ambient ultraviolet radiation (UVR) exposure. Evidence points to a role for type I interferon (IFN-I) in photosensitivity, but mechanistic understanding remains limited. We have shown that photosensitivity in lupus models is at least in part attributable to Langerhans cell (LC) dysfunction. Healthy LCs limit photosensitivity via a disintegrin and metalloprotease 17 (ADAM17), a sheddase that normally limits UVR-induced skin inflammation by releasing soluble epidermal growth factor receptor (EGFR) ligands to support keratinocyte survival. On the other hand, LCs from lesional and even non-lesional lupus model skin show reduced ADAM17 activity and mRNA expression. Non-lesional human lupus skin also showed evidence of LC dysfunction, and, here, we asked how the lupus skin environment contributes to this dysfunction. We show that non-lesional skin in human CLE and multiple photosensitive lupus models share gene expression patterns consistent with a high IFN environment and LC dysfunction. IFN-I inhibits murine and human LC ADAM17 activity, and anti-IFNAR1 in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) are a mediator of ADAM17 activity, and we show that lupus models have reduced UVR-induced LC ROS generation that is restored by anti-IFNAR1. Our findings suggest shared pathogenic mechanisms of photosensitivity in human and murine lupus skin and a model whereby the IFN-I-rich microenvironment in non-lesional lupus skin inhibits UVR-induced ADAM17 activity, predisposing to photosensitivity. Our data also suggest that the beneficial effects of the recently FDA-approved anifrolumab (anti-IFNAR1) on human lupus skin could act in part by restoring LC function.
2023-04-10 | GSE227329 | GEO
Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3â repair exonuclease (Trex)1 cause Aicardi-Goutières syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency. We sorted CD19-positive B cells from spleens of Trex1fl/fl CD19-Cre+ and Trex1fl/fl CD19-Cre- mice and isolated total RNA for library construction to perform mRNA deep sequencing.
2016-08-01 | E-GEOD-77693 | biostudies-arrayexpress
Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3’ repair exonuclease (Trex)1 cause Aicardi-Goutières syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency.
2016-08-01 | GSE77693 | GEO
Project description:Keratinocyte-derived interferon kappa (IFN-κ) is chronically overexpressed in human non-lesional systemic lupus erythematosus (SLE) skin. Recent evidence suggests that epidermal signals instruct the immune system in SLE, but whether epidermal IFN-κ alone is sufficient to drive lupus phenotypes has not been investigated. Here, we show that mice that overexpress Ifnk in the epidermis under the keratin 14 promoter (Ifnk transgenic, TG) on a BALB/c background spontaneously develop cutaneous lupus erythematosus (CLE)-like lesions and systemic immune dysregulation. Lesions show facial predominance, lymphocytic infiltration, and a transcriptional signature reflective of human CLE. Ifnk TG mice exhibit increased immune cell activation and spontaneous signs of systemic autoimmunity with higher anti-dsDNA-antibodies, lymphadenopathy and splenomegaly, but lack signs of renal inflammation. UV exposure enhanced cutaneous inflammation and splenic T cell activation in Ifnk TG mice. Together, we describe a new CLE mouse model that recapitulates features of human CLE and substantiates the role of epidermal IFN-κ as a driver of CLE, photosensitivity and systemic inflammation.
2025-08-11 | GSE290137 | GEO
Project description:Cutaneous lupus erythematosus (CLE) is a photosensitive autoimmune disease characterized by a strong type-I-interferon (IFN) associated inflammation. Keratinocytes are known to determine the interface-dermatitis-pattern in CLE by production of proinflammatory cytokines in the lower epidermis. These cytokines drive a cytotoxic anti-epithelial immune response resulting in keratinocytic cell death and release of endogenous nucleic acids (eNA). We hypothesized that these eNA (RNA- and DNA-motifs) have the capacity to activate innate immune pathways in keratinocytes via pathogen-recognition-receptors (PRR). Gene expression analyses revealed an excessive activation of innate immune response pathways with strong expression of IFN-regulated cytokines in CLE skin lesions. Cultured keratinocytes produce large amounts of these cytokines in response to stimulation of PRR with eNA. UV-stimulation enhances the immunogenicity of eNA and induces CLE-like skin lesions in knockout mice lacking the cytosolic DNase TREX1. Our results provide evidence for a pathogenetic role of endogenous nucleic acids in CLE. They are released within the cytotoxic inflammation along the dermo-epidermal junction and have the capacity to drive the LE-typical inflammation. UV-irradiation supports this inflammation by generation of highly immunostimulatory DNA motifs (8-OHG). These findings explain the photosensitivity of lupus patients and identify pathways of the innate immune system as targets for future therapies.
2017-03-01 | GSE95474 | GEO
Project description:Objective: To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care. Methods: Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering. Results: IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduce the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN- K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs. 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable. Conclusions: IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering. Trial registration number NCT02665364.
2021-10-08 | GSE185047 | GEO
Project description:Skin inflammation and photosensitivity are common manifestations of cutaneous and systemic lupus erythematosus (SLE), yet the underlying mechanisms are poorly understood. Non-lesional SLE skin exhibits increased UVB-driven cell death that persists in culture, supporting a potential role for epigenetic modifications to sustain this phenotype. We thus examined differential DNA methylation of non-lesional SLE vs. healthy control keratinocytes (KC) and identified Hippo signaling as the top significantly differentially methylated pathway, likely driven by hypomethylation of WWC1, a scaffold protein and Hippo pathway regulator. Analysis of non-lesional SLE skin biopsies and SLE keratinocytes in culture confirmed WWC1 overexpression that led to enhanced phosphorylation of YAP resulting in a pro-apoptotic transcriptional profile reflective of decreased YAP/TEAD transcriptional coactivation. Functional studies of UV-mediated apoptosis confirmed a regulatory role for YAP/TEAD interactions, and blockade of overactive Hippo signaling via a LATS1/2 inhibitor abrogated enhanced apoptosis in SLE KCs. Thus, our work identifies a novel mechanistic paradigm in SLE KCs in which aberrant UVB-apoptosis is driven by Hippo signaling via promotion of YAP phosphorylation and restriction of YAP coactivation of TEAD transcriptional activity. Hippo modulation may be a novel target for photosensitivity in SLE and CLE.
2023-07-06 | GSE198972 | GEO