cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model

Xiao, Nanyang; Wei, Jingjing; Xu, Shan; Du, Hekang; Huang, Miaohui; Zhang, Sitong; Ye, Weiwei; Sun, Lijun; Chen, Qi

doi:10.1016/j.jaut.2019.03.001

Cited by 70 publications

(47 citation statements)

References 36 publications

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“…Wang et al [11] showed that there was the association of abnormal elevations in IFIT3 with overactive cyclic GMP-AMP synthase/Stimulator of interferon genes signaling in human systemic lupus erythematosus monocytes. Moreover, It has been showed that cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model [12]. In addition, IRF5 risk variants associate with elevated IRF5 expression and IFN production in SLE blood cells [13].…”

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confidence: 99%

Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

et al. 2021

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Background Systemic lupus erythematosus (SLE) is a multisystemic, chronic inflammatory disease characterized by destructive systemic organ involvement, which could cause the decreased functional capacity, increased morbidity and mortality. Previous studies show that SLE is characterized by autoimmune, inflammatory processes, and tissue destruction. Some seriously-ill patients could develop into lupus nephritis. However, the cause and underlying molecular events of SLE needs to be further resolved. Methods The expression profiles of GSE144390, GSE4588, GSE50772 and GSE81622 were downloaded from the Gene Expression Omnibus (GEO) database to obtain differentially expressed genes (DEGs) between SLE and healthy samples. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were performed by metascape etc. online analyses. The protein–protein interaction (PPI) networks of the DEGs were constructed by GENEMANIA software. We performed Gene Set Enrichment Analysis (GSEA) to further understand the functions of the hub gene, Weighted gene co‐expression network analysis (WGCNA) would be utilized to build a gene co‐expression network, and the most significant module and hub genes was identified. CIBERSORT tools have facilitated the analysis of immune cell infiltration patterns of diseases. The receiver operating characteristic (ROC) analyses were conducted to explore the value of DEGs for SLE diagnosis. Results In total, 6 DEGs (IFI27, IFI44, IFI44L, IFI6, EPSTI1 and OAS1) were screened, Biological functions analysis identified key related pathways, gene modules and co‐expression networks in SLE. IFI27 may be closely correlated with the occurrence of SLE. We found that an increased infiltration of moncytes, while NK cells resting infiltrated less may be related to the occurrence of SLE. Conclusion IFI27 may be closely related pathogenesis of SLE, and represents a new candidate molecular marker of the occurrence and progression of SLE. Moreover immune cell infiltration plays important role in the progession of SLE.

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confidence: 99%

Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

et al. 2021

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“…Western blotting was performed as previously described (Chen et al, 2002; Xiao et al, 2019). Antibodies anti-myeloid differentiation primary response gene 88 (MyD88) (D80F5; #4283), anti-phospho-IKKα/β (Ser176/180) (16A6; #2697), anti-IKKα (#2682), Phospho-IKKα/β (Ser176/180) (16A6, #2697), anti-IκBα (44D4,#4812), anti-Phospho-IκBα (Ser32/36) (5A5, #9246), anti-NF-κB p65 (D14E12, #8242) and anti-Phospho-NF-κB p65 (Ser536) (93H1, #3033) were purchased from Cell Signaling Technology.…”

Section: Methodsmentioning

confidence: 99%

Fucoxanthin, a Marine Xanthophyll Isolated From Conticribra weissflogii ND-8: Preventive Anti-Inflammatory Effect in a Mouse Model of Sepsis

Guo

Huang

et al. 2019

Front. Pharmacol.

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Background: Fucoxanthin (FX), a xanthophyll pigment which occurs in marine brown algae with remarkable biological properties, has been proven to be safe for consumption by animals. Although FX has various pharmacological effects including anti-inflammatory, anti-tumor, anti-obesity, antioxidant, anti-diabetic, anti-malarial, and anti-lipid, in vivo protective effect against sepsis has not been reported. In this study, we aimed at evaluation the efficacy of the FX in a model of sepsis mouse. Methods: FX was successfully isolated from Conticribra weissflogii ND-8 for the first time. The FX was identified by thin-layer chromatography (TLC), high-performance liquid chromatography-mass spectrometry (HPLC-MS), and nuclear magnetic resonance (NMR). Animals were randomly divided into 9 groups, including Sham group (mouse received an intraperitoneal injection of normal saline 1.0 ml/kg), FX-treated (0.1–1.0 ml/kg), Lipopolysaccharide (LPS)-treated (20 mg/kg), FX+LPS-treated (0.1–10.0 mg/kg and 20 mg/kg, respectively), and urinastatin groups (10 4 U/kg). Nuclear factor (NF)-κB activation could be potential treatment for sepsis. NF-κB signaling components were determined by western-blotting. IL-6, IL-1β, TNF-α production, and NF-κB activation were evaluated by ELISA and immunofluorescent staining in vitro . Results: FX was found to decrease the expression of inflammatory cytokines including IL-6, IL-1β, and TNF-α, in a prophylactic manner in the LPS-induced sepsis mouse model. Meanwhile, FX significantly inhibits phosphorylation of the NF-κB signaling pathway induced by LPS at the cellular level and reduces the nuclear translocation of NF-κB. The IC 50 for suppressing the expression of NF-κB was 11.08 ± 0.78 μM in the THP1-Lucia™ NF-κB cells. Furthermore, FX also inhibits the expression of inflammatory factors in a dose-dependent manner with the IC 50 inhibition of IL-6 production was 2.19 ± 0.70 μM in Raw267.4 macrophage cells. It is likely that the molecules with the ability of targeting NF-κB activation and inflammasome assembly, such as fucoxanthin, are interesting subjects to be used for treating sepsis.

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“…The TREX1 gene Mutations have been linked to the autoimmune diseases including Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus (SLE) (Crow et al, 2006). The autoimmune phenotypes derived from the Trex1 gene mutations in mice can be ameliorated by cGAS or STING gene knockout (Gao et al, 2015;Xiao et al, 2019). Since Compound C displays an inhibitory effect on the cGAS-STING-mediated pathway, we further determined its potential beneficial effects against autoimmune phenotypes in the Trex1 mutant cells.…”

Section: Compound C Ameliorates Autoimmune Phenotypes Induced By Lossmentioning

confidence: 99%

Compound C Reducing Interferon Expression by Inhibiting cGAMP Accumulation

et al. 2020

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Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major DNA sensor responsible for cytosolic DNA-mediated innate immune response. Inhibition of cGAS may be an effective strategy for treating autoimmune diseases such as Aicardi-Goutieres syndrome and systemic lupus erythematosus. Compound C (also known as Dorsomorphin) has been annotated as a potent and reversible inhibitor for AMPKs as well as ALK protein kinases. Here, we report a new function of Compound C which can suppress dsDNA-dependent type I interferon induction. These effects were not dependent on the activities of AMPK proteins. In vitro assays and liquid chromatograph-mass spectrometry data show that Compound C has the capability of reducing cGAMP accumulation, suggesting that Compound C may function as a modulator involved in the cGAS-STING-mediated DNA sensing pathway. Furthermore, Compound C is able to rescue the autoimmune phenotypes in a mouse model carrying the Trex1 gene deficiency. These data demonstrate a new and inverse correlation between Compound C and type I interferon production in response to dsDNA signaling.

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cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model

Cited by 70 publications

References 36 publications

Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

Fucoxanthin, a Marine Xanthophyll Isolated From Conticribra weissflogii ND-8: Preventive Anti-Inflammatory Effect in a Mouse Model of Sepsis

Compound C Reducing Interferon Expression by Inhibiting cGAMP Accumulation

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