Multi-omits: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases
Multi-omits: Differential expression of IFN-γ results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases
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DOI：
10.1016/j.jaut.2020.102436
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发表时间：
2020-07-01
影响因子：
12.8
通讯作者：
Young, Howard A.
中科院分区：
文献类型：
--
作者：
Bae, Heekyong R.;Leung, Patrick S. C.;Young, Howard A.
低度慢性炎症是包括自身免疫性疾病在内的免疫功能障碍的关键风险因素。然而，复杂机制的多样性和缺乏相关的小鼠模型限制了我们对慢性炎症确切作用的理解。为了解决这些障碍，我们利用了多组学数据和具有低但慢性IFN-γ表达的独特鼠模型，其通过用随机核苷酸替换IFN-γ mRNA的3' UTR区域中的富含AU的元件（ARE）而产生。在本文中，我们证明了通过纯合或杂合ARE替代在小鼠中IFN-γ的低但差异表达触发了独特的肠道微生物改变，其中改变是女性偏向于自身免疫相关微生物群。代谢组学数据表明，肠道微生物群依赖性代谢物比微生物组分析具有更强的性别差异，特别是那些参与脂肪酸氧化和核受体信号传导的代谢物。更重要的是，纯合子ARE-Del小鼠在色氨酸代谢、胆汁酸和长链脂质代谢方面发生了巨大变化，这些代谢与肠道微生物群和核受体信号传导的相互作用与性别依赖性代谢物相似。与这些发现一致，在雌性纯合子与杂合子ARE-Del小鼠之间的血液和组织特异性基因表达的比较中，可检测到核受体信号传导，包括分子如PPARs、FXR和LXR，作为顶级经典途径。进一步的分析表明，巨噬细胞中失调的自噬对于打破自身耐受和肠道稳态至关重要，而通路与核受体信号传导相互作用以调节炎症反应。总体而言，基于路径的多组学数据整合提供了关于IFN-γ驱动的慢性炎症如何导致具有特定病因病理学特征的自身免疫性疾病发展的系统和细胞见解。
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-gamma, generated by replacement of the AU-rich element (ARE) in the 3' UTR region of IFN-gamma mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-gamma 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-gamma results in the development of autoimmune diseases with specific etiopathological features.