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Diosmetin blocks type Ⅰ interferon 1 signaling by metabolic control of phosphatidylethanolamine [dataset 1]

ABSTRACT: Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. Diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236319 | GEO | 2023/07/06

REPOSITORIES: GEO

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Project description:Abstract Introduction Several environmental stimuli may influence lupus, especially viral infection. We utilize an imiquimod-induced lupus mouse model focusing on TLR7 pathway and use proteomics analysis to figure out the specific pathway related to viral infection and its related protein expressions in splenic B cells, hoping to get an insight on B cell responses to viral infection in lupus model. Material and methods. FVB/N wild type mouse was used treated with imiquimod for 8 weeks to induce lupus symptoms and signs, and splenocytes were retrieved, and B cells were selected and conducted proteomic analysis. The B cells were co-cultured with CD40L+ feeder cells for another one week before Western blot analysis. Panther pathway analysis was used to disclose the pathways activated and protein-protein interactome analyzed by STRING database in this lupus murine model. Results. The lupus model is well established and well demonstrated with serology evidence and pathology proof of lupus-mimic organ damage. Proteomics data of splenic B cells revealed the most important pathways activated (fold enrichment >100) were positive regulation of MDA-5 signaling pathway, negative regulation of IP-10 production, negative regulation of chemokine (C-X-C motif) ligand 2 production and positive regulation of RIG-I signaling pathway. A unique protein-protein interactome containing 10 genes was discovered, within which ISG15, IFIH1, IFIT1, DDX60, and DHX58 have been demonstrated to be downstream effectors of MDA5 signaling. Finally, B cells intracellular cytosolic proteins were determined with Western blot experiment and the MDA5-related pathway activation is still evident. Conclusion. In this experiment, we confirmed that the B cells in lupus murine model focusing on TLR7 pathway were activated through MDA5 signaling pathway, an important RNA sensor implicated in the detection of viral infections and autoimmune. The MDA5 agonists/antagonist RNAs and detailed molecular interactions inside B cells are worthy further investigation for lupus therapy.

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Diosmetin blocks type Ⅰ interferon 1 signaling by metabolic control of phosphatidylethanolamine [dataset 1]

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