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Multi-omics: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases

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العنوان: Multi-omics: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases
المؤلفون: Heekyong R. Bae, Michael Boedigheimer, Seon Min Jeon, Richard A. Fravell, Patrick S.C. Leung, Michael A. Damore, Giorgio Trinchieri, M. Eric Gershwin, Howard A. Young, Deborah L. Hodge, Vishal Thovarai, Andrew A. Welcher, John M. Fenimore, Amiran Dzutsev, Myung-Sook Choi
المصدر: J Autoimmun
بيانات النشر: eScholarship, University of California, 2020.
سنة النشر: 2020
مصطلحات موضوعية: 0301 basic medicine, Male, Cytoplasmic and Nuclear, Autoimmune diseases, Receptors, Cytoplasmic and Nuclear, Gut flora, Mice, Gut dysbiosis, 0302 clinical medicine, Nuclear receptors, Gene expression, Receptors, Immunology and Allergy, 2.1 Biological and endogenous factors, Aetiology, Beta oxidation, 3' Untranslated Regions, Mice, Knockout, Multi-omics, Chronic inflammation, Cell biology, Female, medicine.symptom, Signal Transduction, Sex-difference, Knockout, Sexism, Immunology, Inflammation, Biology, Autoimmune Disease, Article, Autoimmune Diseases, 03 medical and health sciences, Interferon-gamma, medicine, Autophagy, Genetics, Animals, Microbiome, 030203 arthritis & rheumatology, AU Rich Elements, Macrophages, Inflammatory and immune system, Lipid metabolism, biology.organism_classification, Gastrointestinal Microbiome, 030104 developmental biology, Nuclear receptor, Chronic Disease, Dysbiosis, Interferons, Digestive Diseases
الوصف: Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3' UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut microbial alterations, of which alteration is female-biased with autoimmune-associated microbiota. Metabolomics data indicates that gut microbiota-dependent metabolites have more robust sex-differences than microbiome profiling, particularly those involved in fatty acid oxidation and nuclear receptor signaling. More importantly, homozygous ARE-Del mice have dramatic changes in tryptophan metabolism, bile acid and long-chain lipid metabolism, which interact with gut microbiota and nuclear receptor signaling similarly with sex-dependent metabolites. Consistent with these findings, nuclear receptor signaling, encompassing molecules such as PPARs, FXR, and LXRs, was detectable as a top canonical pathway in comparison of blood and tissue-specific gene expression between female homozygous vs heterozygous ARE-Del mice. Further analysis implies that dysregulated autophagy in macrophages is critical for breaking self-tolerance and gut homeostasis, while pathways interact with nuclear receptor signaling to regulate inflammatory responses. Overall, pathway-based integration of multi-omics data provides systemic and cellular insights about how chronic inflammation driven by IFN-γ results in the development of autoimmune diseases with specific etiopathological features.
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https://escholarship.org/uc/item/38j5c3wc
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رقم الانضمام: edsair.doi.dedup.....ffd2452976d050026fa9c2bd879973db
قاعدة البيانات: OpenAIRE
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